Trial Outcomes & Findings for Intrathecal Trastuzumab for Leptomeningeal Metastases in HER2+ Breast Cancer (NCT NCT01325207)

NCT ID: NCT01325207

Last Updated: 2019-09-26

Results Overview

Patients will be treated using a standard 3+3 dose-escalation design for cohorts 1 and 2. This will be followed by an accelerated phase I for cohorts 3 and 4, and then a standard 3 + 3 for the 5th cohort. In the accelerated phase (cohorts 3 and 4), 1 patient will be enrolled per cohort; if a toxicity is seen in that patient then the cohort would be expanded to 6 patients to allow for 1/6 patients per cohort to have a dose limiting toxicity (DLT) before dose escalation. Cohort 5 will enroll a total of 6 patients regardless of the toxicity experienced in patient one. However, if 2 or more DLTs are observed in cohort 5, cohort 4 will be reopened to enroll of a total of 6 patients. Whatever dose is ultimately declared the MTD should have 6 patients total. If 1/6 DLTs are seen in cohort 5 that will be considered the MTD. Dosing is as follows: Cohort 1-10 mg IT Cohort 2-20 mg IT Cohort 3-40 mg IT Cohort 4-60 mg IT Cohort 5-80 mg IT

• Recruitment status: COMPLETED
• Study phase: PHASE1/PHASE2
• Target enrollment: 34 participants
• Primary outcome timeframe: From treatment initiation through the first 4 weeks of treatment.
• Results posted on: 2019-09-26

Participant Flow

The study opened for accrual on April 26, 2011 with first patient being treated August 1, 2011, with an accrual goal of up to 48 patients for phase I/II combined. Amendment 5 added 5th cohort to allow higher dose. The study was suspended April 12, 2014 and reopened on August 28, 2014 for phase II. The study closed to accrual June 2, 2016.

Participant milestones

Measure	Cohort 1 - Trastuzumab 10mg IT 2/Week Intrathecal Trastuzumab 10 mg IT will be administered in Cohort 1 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 2 - Trastuzumab 20mg IT 2/Week Intrathecal Trastuzumab 20 mg IT will be administered in Cohort 2 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 3- Trastuzumab 40mg IT 2/Week Intrathecal Trastuzumab 40 mg IT will be administered in Cohort 3 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 4 - Trastuzumab 60mg IT 2/Week Intrathecal Trastuzumab 60 mg IT will be administered in Cohort 4 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 5 - 80mg IT 2/Week Intrathecal Trastuzumab 80 mg IT will be administered in Cohort 5 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Phase II - Transtuzumab 80mg IT 2/Week Intrathecal Trastuzumab 10 mg IT will be administered in phase II portion of the study. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.
Completed 4 Weeks/1 Cycle of Treatment STARTED	3	3	1	1	7	19
Completed 4 Weeks/1 Cycle of Treatment COMPLETED	3	3	1	1	5	19
Completed 4 Weeks/1 Cycle of Treatment NOT COMPLETED	0	0	0	0	2	0
Completed 8 Weeks/2 Cycles of Treatment STARTED	3	3	1	1	5	19
Completed 8 Weeks/2 Cycles of Treatment COMPLETED	2	2	1	1	3	14
Completed 8 Weeks/2 Cycles of Treatment NOT COMPLETED	1	1	0	0	2	5
Started 9th Week/Cycle 3 of Treatment STARTED	2	2	1	1	3	14
Started 9th Week/Cycle 3 of Treatment COMPLETED	1	0	0	0	3	9
Started 9th Week/Cycle 3 of Treatment NOT COMPLETED	1	2	1	1	0	5
Follow-up Every 3 Months Until Death STARTED	3	3	1	1	7	19
Follow-up Every 3 Months Until Death COMPLETED	3	3	1	1	6	18
Follow-up Every 3 Months Until Death NOT COMPLETED	0	0	0	0	1	1

Reasons for withdrawal

Measure	Cohort 1 - Trastuzumab 10mg IT 2/Week Intrathecal Trastuzumab 10 mg IT will be administered in Cohort 1 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 2 - Trastuzumab 20mg IT 2/Week Intrathecal Trastuzumab 20 mg IT will be administered in Cohort 2 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 3- Trastuzumab 40mg IT 2/Week Intrathecal Trastuzumab 40 mg IT will be administered in Cohort 3 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 4 - Trastuzumab 60mg IT 2/Week Intrathecal Trastuzumab 60 mg IT will be administered in Cohort 4 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 5 - 80mg IT 2/Week Intrathecal Trastuzumab 80 mg IT will be administered in Cohort 5 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Phase II - Transtuzumab 80mg IT 2/Week Intrathecal Trastuzumab 10 mg IT will be administered in phase II portion of the study. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.
Completed 4 Weeks/1 Cycle of Treatment Adverse Event	0	0	0	0	2	0
Completed 8 Weeks/2 Cycles of Treatment Progressive Disease	1	1	0	0	2	5
Started 9th Week/Cycle 3 of Treatment Progressive disease	1	1	1	1	0	4
Started 9th Week/Cycle 3 of Treatment Withdrawal by Subject	0	1	0	0	0	0
Started 9th Week/Cycle 3 of Treatment Adverse Event	0	0	0	0	0	1
Follow-up Every 3 Months Until Death Lost to Follow-up	0	0	0	0	0	1
Follow-up Every 3 Months Until Death Follow-up Considered Complete	0	0	0	0	1	0

Baseline Characteristics

Intrathecal Trastuzumab for Leptomeningeal Metastases in HER2+ Breast Cancer

Baseline characteristics by cohort

Measure	Cohort 1 - Trastuzumab 10mg IT 2/Week n=3 Participants Intrathecal Trastuzumab 10 mg IT will be administered in Cohort 1 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 2 - Trastuzumab 20mg IT 2/Week n=3 Participants Intrathecal Trastuzumab 20 mg IT will be administered in Cohort 2 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 3- Trastuzumab 40mg IT 2/Week n=1 Participants Intrathecal Trastuzumab 40 mg IT will be administered in Cohort 3 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 4 - Trastuzumab 60mg IT 2/Week n=1 Participants Intrathecal Trastuzumab 60 mg IT will be administered in Cohort 4 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 5 - 80mg IT 2/Week n=7 Participants Intrathecal Trastuzumab 80 mg IT will be administered in Cohort 5 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Phase II - Transtuzumab 80mg IT 2/Week n=19 Participants Intrathecal Trastuzumab 10 mg IT will be administered in phase II portion of the study. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Total n=34 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Age, Categorical Between 18 and 65 years	3 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	6 Participants n=21 Participants	17 Participants n=10 Participants	31 Participants n=115 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants	2 Participants n=10 Participants	3 Participants n=115 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	7 Participants n=21 Participants	18 Participants n=10 Participants	32 Participants n=115 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=10 Participants	2 Participants n=115 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=10 Participants	2 Participants n=115 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	2 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	7 Participants n=21 Participants	18 Participants n=10 Participants	32 Participants n=115 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=10 Participants	1 Participants n=115 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	3 Participants n=10 Participants	3 Participants n=115 Participants
Race (NIH/OMB) White	3 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	7 Participants n=21 Participants	14 Participants n=10 Participants	29 Participants n=115 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=10 Participants	1 Participants n=115 Participants
Region of Enrollment United States	3 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	7 Participants n=21 Participants	19 Participants n=10 Participants	34 Participants n=115 Participants

PRIMARY outcome

Timeframe: From treatment initiation through the first 4 weeks of treatment.

Patients will be treated using a standard 3+3 dose-escalation design for cohorts 1 and 2. This will be followed by an accelerated phase I for cohorts 3 and 4, and then a standard 3 + 3 for the 5th cohort. In the accelerated phase (cohorts 3 and 4), 1 patient will be enrolled per cohort; if a toxicity is seen in that patient then the cohort would be expanded to 6 patients to allow for 1/6 patients per cohort to have a dose limiting toxicity (DLT) before dose escalation. Cohort 5 will enroll a total of 6 patients regardless of the toxicity experienced in patient one. However, if 2 or more DLTs are observed in cohort 5, cohort 4 will be reopened to enroll of a total of 6 patients. Whatever dose is ultimately declared the MTD should have 6 patients total. If 1/6 DLTs are seen in cohort 5 that will be considered the MTD.

Dosing is as follows:

Cohort 1-10 mg IT Cohort 2-20 mg IT Cohort 3-40 mg IT Cohort 4-60 mg IT Cohort 5-80 mg IT

Outcome measures

Measure	Cohort 1 - Trastuzumab 10mg IT 2/Week n=3 Participants Intrathecal Trastuzumab 10 mg IT will be administered in Cohort 1 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 2 - Trastuzumab 20mg IT 2/Week n=3 Participants Intrathecal Trastuzumab 20 mg IT will be administered in Cohort 2 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 3- Trastuzumab 40mg IT 2/Week n=1 Participants Intrathecal Trastuzumab 40 mg IT will be administered in Cohort 3 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 4 - Trastuzumab 60mg IT 2/Week n=1 Participants Intrathecal Trastuzumab 60 mg IT will be administered in Cohort 4 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 5 - 80mg IT 2/Week n=7 Participants Intrathecal Trastuzumab 80 mg IT will be administered in Cohort 5 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.
Number of Dose Limiting Toxicities (DLT) of IT Trastuzumab in Sequential Cohorts of Escalating Doses for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer.	0 DLTs	0 DLTs	0 DLTs	0 DLTs	1 DLTs

PRIMARY outcome

Timeframe: Baseline then at 4 weeks, 8 weeks and then every 8 weeks +/- 3 days, until disease progression or toxicity,range of cycles completed 1-22 cycles where 1 cycle = 28 days.

Population: All patients were assessed for response. Patients unable to be assessed were determined to have progressive disease and counted. Cohort results for this outcome measure were analysed combined and at the MTD of 80mg IT (Cohort 5 + phase II). The objective was to determine preliminary response data for this treatment combination.

Best response will be assessed using a combination CSF cytology assessment, radiographic assessment and clinical function assessments. Best response will be defined as the best response seen during treatment as compared to baseline that is confirmed on subsequent response assessment.

Outcome measures

Measure	Cohort 1 - Trastuzumab 10mg IT 2/Week n=34 Participants Intrathecal Trastuzumab 10 mg IT will be administered in Cohort 1 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 2 - Trastuzumab 20mg IT 2/Week n=26 Participants Intrathecal Trastuzumab 20 mg IT will be administered in Cohort 2 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 3- Trastuzumab 40mg IT 2/Week Intrathecal Trastuzumab 40 mg IT will be administered in Cohort 3 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 4 - Trastuzumab 60mg IT 2/Week Intrathecal Trastuzumab 60 mg IT will be administered in Cohort 4 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 5 - 80mg IT 2/Week Intrathecal Trastuzumab 80 mg IT will be administered in Cohort 5 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.
Best Response to IT Trastuzumab: Radiological, Cytological and Clinical in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. Complete Response	0 Participants	0 Participants	—	—	—
Best Response to IT Trastuzumab: Radiological, Cytological and Clinical in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. Partial Response	6 Participants	5 Participants	—	—	—
Best Response to IT Trastuzumab: Radiological, Cytological and Clinical in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. Stable Disease	18 Participants	13 Participants	—	—	—
Best Response to IT Trastuzumab: Radiological, Cytological and Clinical in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. Progressive Disease	10 Participants	8 Participants	—	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: CSF analysis for cytology will be done every 2 weeks when CSF is obtained for PK and then every 4 weeks

Patients may need a CSF flow study at the discretion of the treating principal investigator. If a spinal block is seen by CSF flow study or MRI, it will need local RT prior to treatment. Concurrent radiation is not allowed.

Outcome measures

Outcome data not reported

POST_HOC outcome

Timeframe: At 6 and 12 months from start of treatment

Population: Cohort results for this outcome measure were analyzed both combined and for patients treated at the MTD dose of 80mg IT as the objective was to determine preliminary data on PFS of patients with this drug combination.

Progression Free Survival (PFS) will be measured from the time of treatment initiation until the first documentation of progression. To estimate the probability of PFS at 6 months and 12 months, Kaplan-Meier curves will be calculated and PFS at 6 months and 12 months will be determined from the progression-free survival curve. Progression will be defined as worsening clinical signs or development of new clinical symptoms that the Investigator feels can be attributed to Leptomeningeal disease.

Outcome measures

Measure	Cohort 1 - Trastuzumab 10mg IT 2/Week n=34 Participants Intrathecal Trastuzumab 10 mg IT will be administered in Cohort 1 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 2 - Trastuzumab 20mg IT 2/Week n=26 Participants Intrathecal Trastuzumab 20 mg IT will be administered in Cohort 2 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 3- Trastuzumab 40mg IT 2/Week Intrathecal Trastuzumab 40 mg IT will be administered in Cohort 3 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 4 - Trastuzumab 60mg IT 2/Week Intrathecal Trastuzumab 60 mg IT will be administered in Cohort 4 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 5 - 80mg IT 2/Week Intrathecal Trastuzumab 80 mg IT will be administered in Cohort 5 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.
Progression Free Survival (PRS) at 6 Months and at 12 Months in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. PFS at 6 months	0.235 Probability of Survival	0.269 Probability of Survival	—	—	—
Progression Free Survival (PRS) at 6 Months and at 12 Months in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. PFS at 12 months	0.118 Probability of Survival	0.115 Probability of Survival	—	—	—

POST_HOC outcome

Timeframe: At 6 and 12 months from start of treatment

Population: Cohort results for this outcome measure were analyzed both combined and for patients treated at the MTD dose of 80mg IT as the objective was to determine preliminary data on OS of patients with this drug combination.

Overall Survival (OS) will be measured from the time of treatment initiation until death from any cause. To estimate OS probability at 6 and 12 months, Kaplan-Meier curves will be calculated and OS at 612 months will be determined from the overall survival curve.

Outcome measures

Measure	Cohort 1 - Trastuzumab 10mg IT 2/Week n=34 Participants Intrathecal Trastuzumab 10 mg IT will be administered in Cohort 1 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 2 - Trastuzumab 20mg IT 2/Week n=26 Participants Intrathecal Trastuzumab 20 mg IT will be administered in Cohort 2 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 3- Trastuzumab 40mg IT 2/Week Intrathecal Trastuzumab 40 mg IT will be administered in Cohort 3 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 4 - Trastuzumab 60mg IT 2/Week Intrathecal Trastuzumab 60 mg IT will be administered in Cohort 4 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 5 - 80mg IT 2/Week Intrathecal Trastuzumab 80 mg IT will be administered in Cohort 5 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.
Overall Survival (OS) at 6 and 12 Months in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. OS at 12 months	0.406 Probability of Survival	0.458 Probability of Survival	—	—	—
Overall Survival (OS) at 6 and 12 Months in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. OS at 6 months	0.562 Probability of Survival	0.542 Probability of Survival	—	—	—

POST_HOC outcome

Timeframe: From start of treatment, and during treatment until progressive disease for up to 30 months.

Population: Cohort results for this outcome measure were analyzed both combined and for patients treated at the MTD dose of 80mg IT as the objective was to determine preliminary data on PFS of patients with this drug combination

Progression Free Survival (PFS) will be measured from the time of treatment initiation until the first documentation of progression. To estimate PFS, Kaplan-Meier curves will be calculated and the median PFS will be determined from the progression-free survival curve. Progression will be defined as worsening clinical signs or development of new clinical symptoms that the Investigator feels can be attributed to Leptomeningeal disease.

Outcome measures

Measure	Cohort 1 - Trastuzumab 10mg IT 2/Week n=34 Participants Intrathecal Trastuzumab 10 mg IT will be administered in Cohort 1 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 2 - Trastuzumab 20mg IT 2/Week n=26 Participants Intrathecal Trastuzumab 20 mg IT will be administered in Cohort 2 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 3- Trastuzumab 40mg IT 2/Week Intrathecal Trastuzumab 40 mg IT will be administered in Cohort 3 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 4 - Trastuzumab 60mg IT 2/Week Intrathecal Trastuzumab 60 mg IT will be administered in Cohort 4 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 5 - 80mg IT 2/Week Intrathecal Trastuzumab 80 mg IT will be administered in Cohort 5 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.
Median Progression Free Survival (PFS) in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer.	1.885 Months Interval 1.541 to 3.738	2.148 Months Interval 1.016 to 7.344	—	—	—

POST_HOC outcome

Timeframe: From start of treatment until death from any cause for up to 60 months.

Population: Cohort results for this outcome measure were analyzed both combined and for patients treated at the MTD dose of 80mg IT as the objective was to determine preliminary data on OS of patients with this drug combination

Overall Survival (OS) will be measured from start of treatment until death from any cause. To estimate OS, Kaplan-Meier curves will be calculated and median OS will be determined from the progression-free survival curve.

Outcome measures

Measure	Cohort 1 - Trastuzumab 10mg IT 2/Week n=34 Participants Intrathecal Trastuzumab 10 mg IT will be administered in Cohort 1 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 2 - Trastuzumab 20mg IT 2/Week n=26 Participants Intrathecal Trastuzumab 20 mg IT will be administered in Cohort 2 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 3- Trastuzumab 40mg IT 2/Week Intrathecal Trastuzumab 40 mg IT will be administered in Cohort 3 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 4 - Trastuzumab 60mg IT 2/Week Intrathecal Trastuzumab 60 mg IT will be administered in Cohort 4 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 5 - 80mg IT 2/Week Intrathecal Trastuzumab 80 mg IT will be administered in Cohort 5 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.
Median Overall Survival (OS) in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer.	8.738 percentage of patients Interval 5.607 to 17.311	8.328 percentage of patients Interval 5.148 to 19.541	—	—	—

Adverse Events

Cohort 1 - Trastuzumab 10mg IT 2/Week

Serious events: 1 serious events

Other events: 3 other events

Deaths: 3 deaths

Cohort 2 - Trastuzumab 20mg IT 2/Week

Serious events: 2 serious events

Other events: 3 other events

Deaths: 3 deaths

Cohort 3- Trastuzumab 40mg IT 2/Week

Serious events: 1 serious events

Other events: 1 other events

Deaths: 1 deaths

Cohort 4 - Trastuzumab 60mg IT 2/Week

Serious events: 1 serious events

Other events: 1 other events

Deaths: 1 deaths

Cohort 5 - 80mg IT 2/Week

Serious events: 3 serious events

Other events: 7 other events

Deaths: 5 deaths

Phase II - Transtuzumab 80mg IT 2/Week

Serious events: 13 serious events

Other events: 19 other events

Deaths: 17 deaths

Serious adverse events

Measure	Cohort 1 - Trastuzumab 10mg IT 2/Week n=3 participants at risk Intrathecal Trastuzumab 10 mg IT will be administered in Cohort 1 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 2 - Trastuzumab 20mg IT 2/Week n=3 participants at risk Intrathecal Trastuzumab 20 mg IT will be administered in Cohort 2 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 3- Trastuzumab 40mg IT 2/Week n=1 participants at risk Intrathecal Trastuzumab 40 mg IT will be administered in Cohort 3 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 4 - Trastuzumab 60mg IT 2/Week n=1 participants at risk Intrathecal Trastuzumab 60 mg IT will be administered in Cohort 4 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 5 - 80mg IT 2/Week n=7 participants at risk Intrathecal Trastuzumab 80 mg IT will be administered in Cohort 5 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Phase II - Transtuzumab 80mg IT 2/Week n=19 participants at risk Intrathecal Trastuzumab 10 mg IT will be administered in phase II portion of the study. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.
Cardiac disorders Pericardial effusion	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Dysphasia	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Seizure	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	10.5% 2/19 • Number of events 2 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Infections and infestations Chemical meningitis	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	10.5% 2/19 • Number of events 2 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Worsening Mental Status	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Metabolism and nutrition disorders Hyponatremia	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Number of events 2 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Abdominal muscle wall hemorrhage	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Syncope	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Respiratory, thoracic and mediastinal disorders Death due to aspiration pneumonia	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Dehydration	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Gastroenteritis	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Number of events 2 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Respiratory, thoracic and mediastinal disorders Esophagitis	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Vasivagal reaction	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Vomiting	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Colonic perforation	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Abdominal pain	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Vascular disorders Thromboembolic event (DVT)	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Death due to progressive disease	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Musculoskeletal and connective tissue disorders Pain in back and extremities	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Infections and infestations Lung infection	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Clinical deterioration	33.3% 1/3 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Infections and infestations Wound infection	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	33.3% 1/3 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Worsening neurological symptoms	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	66.7% 2/3 • Number of events 2 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Infections and infestations Enterocolitis infectious	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Musculoskeletal and connective tissue disorders Muscle weakness	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Hydrocephalus	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Arachnoiditis	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Number of events 1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.

Other adverse events

Measure	Cohort 1 - Trastuzumab 10mg IT 2/Week n=3 participants at risk Intrathecal Trastuzumab 10 mg IT will be administered in Cohort 1 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 2 - Trastuzumab 20mg IT 2/Week n=3 participants at risk Intrathecal Trastuzumab 20 mg IT will be administered in Cohort 2 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 3- Trastuzumab 40mg IT 2/Week n=1 participants at risk Intrathecal Trastuzumab 40 mg IT will be administered in Cohort 3 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 4 - Trastuzumab 60mg IT 2/Week n=1 participants at risk Intrathecal Trastuzumab 60 mg IT will be administered in Cohort 4 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Cohort 5 - 80mg IT 2/Week n=7 participants at risk Intrathecal Trastuzumab 80 mg IT will be administered in Cohort 5 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.	Phase II - Transtuzumab 80mg IT 2/Week n=19 participants at risk Intrathecal Trastuzumab 10 mg IT will be administered in phase II portion of the study. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days.
Investigations Alanine Aminotransferase Increased	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	28.6% 2/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	26.3% 5/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Investigations Alkaline Phosphatase Increased	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	15.8% 3/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Investigations Aspartate Aminotransferase Increased	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	42.9% 3/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	15.8% 3/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Blood and lymphatic system disorders Anemia	66.7% 2/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	66.7% 2/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	57.1% 4/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	47.4% 9/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Cardiac disorders Palpitations	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Ear and labyrinth disorders Hearing impaired	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Ear and labyrinth disorders Tinnitus	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Eye disorders Blurred vision	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Abdominal pain	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Constipation	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	10.5% 2/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Diarrhea	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	66.7% 2/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	10.5% 2/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Dry mouth	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Dysphagia	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Fecal incontinence	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Hemorrhoids	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	10.5% 2/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Mucositis oral	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Nausea	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	66.7% 2/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	42.9% 3/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	10.5% 2/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Upper gastrointestinal hemorrhage	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Vomiting	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	66.7% 2/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	15.8% 3/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Decreased appetite	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Gastrointestinal disorders Chills	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
General disorders Edema in limbs	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
General disorders Edema in head	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
General disorders Fatigue	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	42.9% 3/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	21.1% 4/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
General disorders Fever	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
General disorders Flu like symptoms	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
General disorders Gait disturbance	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	10.5% 2/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
General disorders Non-cardiac Chest Pain	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
General disorders Pain	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	10.5% 2/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Infections and infestations Lung infection	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Infections and infestations Paronychia	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Infections and infestations Skin infection	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Infections and infestations Urinary tract infection	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Infections and infestations Vaginal infection	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Injury, poisoning and procedural complications Fall	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	10.5% 2/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Injury, poisoning and procedural complications Dermatitis radiation	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Investigations Activated Partial Thromboplastin Time Prolonged	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Investigations Blood Antidiuretic Hormone Abnormal	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Investigations Blood Bilirubin Increased	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Investigations Lymphocyte Count Decreased	66.7% 2/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	42.1% 8/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Investigations Neutrophil Count Decreased	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Investigations Platelet Count Decreased	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	26.3% 5/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Investigations White Blood Cell Decreased	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	31.6% 6/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Metabolism and nutrition disorders Dehydration	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	10.5% 2/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Metabolism and nutrition disorders Hyperglycemia	66.7% 2/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	66.7% 2/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	57.1% 4/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	21.1% 4/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Metabolism and nutrition disorders Hypernatremia	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Metabolism and nutrition disorders Hypoalbuminemia	66.7% 2/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	66.7% 2/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	42.9% 3/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	36.8% 7/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Metabolism and nutrition disorders Hypocalcemia	100.0% 3/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	28.6% 2/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	15.8% 3/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Metabolism and nutrition disorders Hypoglycemia	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Metabolism and nutrition disorders Hypokalemia	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	66.7% 2/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	28.6% 2/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	15.8% 3/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Metabolism and nutrition disorders Hypomagnesemia	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	10.5% 2/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Metabolism and nutrition disorders Hyponatremia	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	71.4% 5/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	15.8% 3/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Musculoskeletal and connective tissue disorders Back Pain	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Musculoskeletal and connective tissue disorders Buttock Pain	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Musculoskeletal and connective tissue disorders Generalized Muscle Weakness	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Musculoskeletal and connective tissue disorders Muscle Weakness Lower Limb	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	10.5% 2/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Musculoskeletal and connective tissue disorders Muscle Weakness Upper Limb	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Musculoskeletal and connective tissue disorders Neck Pain	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Musculoskeletal and connective tissue disorders Pain in Extremity	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Abducens Nerve Disorder	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Dizziness	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	28.6% 2/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Dysgeusia	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Headaches	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	28.6% 2/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	15.8% 3/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Lethargy	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Memory Impairment	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Meningismus	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	10.5% 2/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Involuntary Movements	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Oculomotor Nerve Disorder	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Peripheral Sensory Neuropathy	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Seizure	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	15.8% 3/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Syncope	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Paresthesia	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Aphasia	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Nervous system disorders Gait difficulty	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Psychiatric disorders Anxiety	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Psychiatric disorders Confusion	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Psychiatric disorders Insomnia	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Renal and urinary disorders Urinary incontinence	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	10.5% 2/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Renal and urinary disorders Urinary Frequency	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Respiratory, thoracic and mediastinal disorders Allergic Rhinitis	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Respiratory, thoracic and mediastinal disorders Epistaxis	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Respiratory, thoracic and mediastinal disorders Hoarseness	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Respiratory, thoracic and mediastinal disorders Respiratory Failure	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Skin and subcutaneous tissue disorders Alopecia	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	10.5% 2/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Skin and subcutaneous tissue disorders Dry Skin	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Skin and subcutaneous tissue disorders Pain of Skin	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Skin and subcutaneous tissue disorders Rash Acneiform	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Skin and subcutaneous tissue disorders Rash Maculo-papular	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Skin and subcutaneous tissue disorders Hand and Foot Syndrome	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	100.0% 1/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Vascular disorders Hematuria	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Vascular disorders Hypertension	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	85.7% 6/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Vascular disorders Hypotension	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	5.3% 1/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Vascular disorders Hot Flashes	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	14.3% 1/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Vascular disorders Lymphedema	33.3% 1/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
Vascular disorders Thromboembolic Event	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/3 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/1 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	0.00% 0/7 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.	10.5% 2/19 • Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.

Additional Information

Jeffrey Raizer, MD

Northwestern University

Email: Jeffrey.Raizer@nm.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place