Trial Outcomes & Findings for A Dose-Escalation Study Evaluating the Combination of Trastuzumab Emtansine (T-DM1) With Neratinib in Women With Metastatic HER2-Positive Breast Cancer (NCT NCT02236000)

Last Updated: 2023-01-26

Results Overview

If 1 of 3 patients in this cohort experiences a dose limiting toxicity (DLT), 3 more patients will be added at the same dose level. If 0 of 3 initial patients or 1 of 6 patients in an expanded cohort experiences a DLT, the dose for the next cohort will be escalated to dose level 2; otherwise, the combination will be considered too toxic.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

49 participants

Primary outcome timeframe

Day 1, 8, and 15 of cycle 1.

Results posted on

2023-01-26

Participant Flow

Phase 1 consisted of 4 parts involving increasing doses of Neratinib in each part. Together, 27 patients were enrolled. In Phase II, 22 patients were enrolled. Therefore 49 patients were enrolled in both phases of the trial.

Endpoint information is not available for 1 patient.

Participant milestones

Participant milestones
Measure	Phase 1-Neratinib 120mg; T-DM1 3.6mg/kg Dose Level 1- Neratinib 120mg T-DM1 3.6.mg/kg	Phase 1-Neratinib 160 mg; T-DM1 3.6mg/kg Dose Level 2- Neratinib 160 mg T-DM1 3.6mg/kg	Phase 1-Neratinib 200mg; T-DM1 3.6mg/kg Dose Level 3- Neratinib 200mg T-DM1 3.6mg/kg	Phase 1 Neratinib 240; T-DM1 3.6mg/kg Dose Level 4- Neratinib 240mg T-DM1 3.6 mg/kg	Neratinib and T-DM1 Part 2 (Phase II) Dose-evaluation Phase (Part 2)-Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy. Dose-evaluation Phase (Part 2)-Trastuzumab ematansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 ever 21 days.
Overall Study STARTED	6	10	8	3	22
Overall Study COMPLETED	6	10	8	3	22
Overall Study NOT COMPLETED	0	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Dose-Escalation Study Evaluating the Combination of Trastuzumab Emtansine (T-DM1) With Neratinib in Women With Metastatic HER2-Positive Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase 1-Neratinib 120mg; T-DM1 3.6mg/kg n=6 Participants Dose Level 1-Neratinib 120mg T-DM1 3.6mg/kg	Phase 1-Neratinib160mg; T-DM1 3.6mg/kg n=10 Participants Dose Level 2-Neratinib 160mg T-DM1 3.6mg/kg	Phase 1-Neratinib 200mg; T-DM1 3.6mg/kg n=8 Participants Dose Level 3-Neratinib 200mg T-DM1 3.6 mg/kg	Phase 1 Neratinib 240mg; T-DM1 3.6mg/kg n=3 Participants Dose Level 4-Neratinib 240mg T-DM1 3.6mg/kg	Neratinib and T-DM1 Part 2 (Phase II) n=22 Participants Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy. Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.	Total n=49 Participants Total of all reporting groups
Age, Continuous	47.8 years STANDARD_DEVIATION 15.30 • n=5 Participants	51.1 years STANDARD_DEVIATION 13.24 • n=7 Participants	51.0 years STANDARD_DEVIATION 9.40 • n=5 Participants	42.0 years STANDARD_DEVIATION 7.00 • n=4 Participants	55.5 years STANDARD_DEVIATION 10.35 • n=21 Participants	52.08 years STANDARD_DEVIATION 11.25 • n=10 Participants
Sex: Female, Male Female	6 Participants n=5 Participants	10 Participants n=7 Participants	8 Participants n=5 Participants	3 Participants n=4 Participants	22 Participants n=21 Participants	49 Participants n=10 Participants
Sex: Female, Male Male	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
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants	3 Participants n=10 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants n=5 Participants	9 Participants n=7 Participants	8 Participants n=5 Participants	3 Participants n=4 Participants	20 Participants n=21 Participants	46 Participants n=10 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
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	1 Participants n=21 Participants	1 Participants n=10 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants	2 Participants n=10 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
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	2 Participants n=10 Participants
Race (NIH/OMB) White	6 Participants n=5 Participants	6 Participants n=7 Participants	6 Participants n=5 Participants	3 Participants n=4 Participants	20 Participants n=21 Participants	41 Participants n=10 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	3 Participants n=10 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	0 Participants n=10 Participants

PRIMARY outcome

Timeframe: Day 1, 8, and 15 of cycle 1.

Population: ITT patients who are evaluable for toxicity during the 1st cycle (patients who completed Cycle 1 or had a DLT) of the Phase 1 portion of the study.

Outcome measures

Outcome measures
Measure	Phase 1 Neratinib 120mg; T-DM1 3.6mg/kg n=6 Participants Dose Level 1-Neratinib 120mg T-DM1 3.6mg/kg	Phase 1 Neratinib 160mg; T-DM1 3.6mg/kg n=9 Participants Dose Level 2-Neratinib 160mg T-DM1 3.6mg/kg	Phase 1 Neratinib 200mg; T-DM1 3.6mg/kg n=8 Participants Dose Level 3-Neratinib 200mg T-DM1 3.6mg/kg	Phase 1 Neratinib 240mg; T-DM1 3.6mg/kg n=3 Participants Dose Level 4-Neratinib 240mg T-DM1 3.6mg/kg	Neratinib and T-DM1 n=26 Participants Neratinib: Dose-Escalation Phase (Part 1) - Neratinib Dose-escalation will proceed on the basis of DLT during Cycle 1 starting at 120 mg/day. Dose level 1: 120 mg/day; Dose level 2: 160 mg/day; Dose level 3: 200 mg/day; Dose level 4: 240 mg/day Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy T-DM1: Dose-Escalation Phase (Part 1) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days. Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.	Neratinib and T-DM1 Part 2 (Phase II) Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy. Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.
Number of Evaluable Patients With Dose Limiting Toxicity Events in Phase 1	1 Participants	0 Participants	4 Participants	2 Participants	7 Participants	—

PRIMARY outcome

Timeframe: Every 42 days after the start of protocol therapy through disease progression, approximately 2 years

Population: ITT poplulation

Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Outcome measures

Outcome measures
Measure	Phase 1 Neratinib 120mg; T-DM1 3.6mg/kg n=22 Participants Dose Level 1-Neratinib 120mg T-DM1 3.6mg/kg	Phase 1 Neratinib 160mg; T-DM1 3.6mg/kg Dose Level 2-Neratinib 160mg T-DM1 3.6mg/kg	Phase 1 Neratinib 200mg; T-DM1 3.6mg/kg Dose Level 3-Neratinib 200mg T-DM1 3.6mg/kg	Phase 1 Neratinib 240mg; T-DM1 3.6mg/kg Dose Level 4-Neratinib 240mg T-DM1 3.6mg/kg	Neratinib and T-DM1 Neratinib: Dose-Escalation Phase (Part 1) - Neratinib Dose-escalation will proceed on the basis of DLT during Cycle 1 starting at 120 mg/day. Dose level 1: 120 mg/day; Dose level 2: 160 mg/day; Dose level 3: 200 mg/day; Dose level 4: 240 mg/day Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy T-DM1: Dose-Escalation Phase (Part 1) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days. Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.	Neratinib and T-DM1 Part 2 (Phase II) Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy. Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.
Overall Response Rate (ORR) by Measurement of Target Lesions in Phase II	31.8 percentage of participants Interval 15.99 to 51.55	—	—	—	—	—

SECONDARY outcome

Timeframe: Every 42 days after the start of protocol therapy through disease progression, approximately 2 years

Population: ITT population

Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Outcome measures

Outcome measures
Measure	Phase 1 Neratinib 120mg; T-DM1 3.6mg/kg n=6 Participants Dose Level 1-Neratinib 120mg T-DM1 3.6mg/kg	Phase 1 Neratinib 160mg; T-DM1 3.6mg/kg n=10 Participants Dose Level 2-Neratinib 160mg T-DM1 3.6mg/kg	Phase 1 Neratinib 200mg; T-DM1 3.6mg/kg n=8 Participants Dose Level 3-Neratinib 200mg T-DM1 3.6mg/kg	Phase 1 Neratinib 240mg; T-DM1 3.6mg/kg n=3 Participants Dose Level 4-Neratinib 240mg T-DM1 3.6mg/kg	Neratinib and T-DM1 n=27 Participants Neratinib: Dose-Escalation Phase (Part 1) - Neratinib Dose-escalation will proceed on the basis of DLT during Cycle 1 starting at 120 mg/day. Dose level 1: 120 mg/day; Dose level 2: 160 mg/day; Dose level 3: 200 mg/day; Dose level 4: 240 mg/day Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy T-DM1: Dose-Escalation Phase (Part 1) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days. Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.	Neratinib and T-DM1 Part 2 (Phase II) n=22 Participants Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy. Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.
Progression-free Survival (PFS) Time From Start of Study Therapy to Disease Progression or Death From Any Cause	40 weeks Interval 22.0 to 72.29	15.4 weeks Interval 2.0 to Small sample size results in infinite upper 95% confidence bound.	8.86 weeks Interval 3.0 to 80.0	9.00 weeks Interval 0.0 to Small sample size results in infinite upper 95% confidence bound.	22 weeks Interval 3.29 to Small sample size results in infinite upper 95% confidence bound.	27 weeks Interval 8.0 to 61.0

SECONDARY outcome

Timeframe: Day 1, 8, 15 of cycle one, day 1 of each subsequent cycle, at the end of protocol therapy and 30 days following the end of protocol therapy. Duration of therapy varied across patients from a few days to a couple of years.

Population: ITT population

Summary of frequency and severity of serious adverse events,

Outcome measures

Outcome measures
Measure	Phase 1 Neratinib 120mg; T-DM1 3.6mg/kg n=6 Participants Dose Level 1-Neratinib 120mg T-DM1 3.6mg/kg	Phase 1 Neratinib 160mg; T-DM1 3.6mg/kg n=10 Participants Dose Level 2-Neratinib 160mg T-DM1 3.6mg/kg	Phase 1 Neratinib 200mg; T-DM1 3.6mg/kg n=8 Participants Dose Level 3-Neratinib 200mg T-DM1 3.6mg/kg	Phase 1 Neratinib 240mg; T-DM1 3.6mg/kg n=3 Participants Dose Level 4-Neratinib 240mg T-DM1 3.6mg/kg	Neratinib and T-DM1 n=22 Participants Neratinib: Dose-Escalation Phase (Part 1) - Neratinib Dose-escalation will proceed on the basis of DLT during Cycle 1 starting at 120 mg/day. Dose level 1: 120 mg/day; Dose level 2: 160 mg/day; Dose level 3: 200 mg/day; Dose level 4: 240 mg/day Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy T-DM1: Dose-Escalation Phase (Part 1) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days. Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.	Neratinib and T-DM1 Part 2 (Phase II) Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy. Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.
Adverse Events Experienced by Participants as a Measure of Toxicity	1 Participants	3 Participants	3 Participants	0 Participants	10 Participants	—

SECONDARY outcome

Timeframe: Every 63 days after the start of study therapy until disease progression or until 30 days following the end of protocol therapy if due to another cause. Duration of therapy varied across patients from a few days to a couple of years.

Population: ITT population

Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions assessed by MRI or CT; Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of new lesions; Stable Disease (SD) otherwise; Clinical Benefit (CB) = CR+PR+SD (confirmation of response not required).

Outcome measures

Outcome measures
Measure	Phase 1 Neratinib 120mg; T-DM1 3.6mg/kg n=22 Participants Dose Level 1-Neratinib 120mg T-DM1 3.6mg/kg	Phase 1 Neratinib 160mg; T-DM1 3.6mg/kg Dose Level 2-Neratinib 160mg T-DM1 3.6mg/kg	Phase 1 Neratinib 200mg; T-DM1 3.6mg/kg Dose Level 3-Neratinib 200mg T-DM1 3.6mg/kg	Phase 1 Neratinib 240mg; T-DM1 3.6mg/kg Dose Level 4-Neratinib 240mg T-DM1 3.6mg/kg	Neratinib and T-DM1 Neratinib: Dose-Escalation Phase (Part 1) - Neratinib Dose-escalation will proceed on the basis of DLT during Cycle 1 starting at 120 mg/day. Dose level 1: 120 mg/day; Dose level 2: 160 mg/day; Dose level 3: 200 mg/day; Dose level 4: 240 mg/day Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy T-DM1: Dose-Escalation Phase (Part 1) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days. Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.	Neratinib and T-DM1 Part 2 (Phase II) Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy. Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.
Clinical Benefit Rate (Phase II)	12 Participants	—	—	—	—	—

Adverse Events

Phase 1 Neratinib 120mg; T-DM1 3.6mg/kg

Serious events: 1 serious events

Other events: 6 other events

Deaths: 0 deaths

Phase 1 Neratinib 160mg; T-DM1 3.6mg/kg

Serious events: 3 serious events

Other events: 10 other events

Deaths: 1 deaths

Phase 1 Neratinib 200mg; T-DM1 3.6mg/kg

Serious events: 3 serious events

Other events: 8 other events

Deaths: 0 deaths

Phase 1 Neratinib 240mg; T-DM1 3.6mg/kg

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Neratinib and T-DM1 Part 1 (Phase 1)

Serious events: 7 serious events

Other events: 27 other events

Deaths: 1 deaths

Neratinib and T-DM1Part 1 (Phase 2)

Serious events: 10 serious events

Other events: 22 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	Phase 1 Neratinib 120mg; T-DM1 3.6mg/kg n=6 participants at risk Neratinib 120mg T-DM1 3.6mg/kg	Phase 1 Neratinib 160mg; T-DM1 3.6mg/kg n=10 participants at risk Neratinib 160mg T-DM1 3.6mg/kg	Phase 1 Neratinib 200mg; T-DM1 3.6mg/kg n=8 participants at risk Neratinib 200mg T-DM1 3.6mg/kg	Phase 1 Neratinib 240mg; T-DM1 3.6mg/kg n=3 participants at risk Neratinib 240mg T-DM1 3.6mg/kg	Neratinib and T-DM1 Part 1 (Phase 1) n=27 participants at risk Neratinib: Dose-Escalation Phase (Part 1) - Neratinib Dose-escalation will proceed on the basis of DLT during Cycle 1 starting at 120 mg/day. Dose level 1: 120 mg/day; Dose level 2: 160 mg/day; Dose level 3: 200 mg/day; Dose level 4: 240 mg/day T-DM1: Dose-Escalation Phase (Part 1) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.	Neratinib and T-DM1Part 1 (Phase 2) n=22 participants at risk Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy. Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.
Renal and urinary disorders Renal failure	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	3.7% 1/27 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Injury, poisoning and procedural complications Infusion related reaction	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	4.5% 1/22 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Investigations Blood creatinine increased	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	3.7% 1/27 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	4.5% 1/22 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	4.5% 1/22 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	4.5% 1/22 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Nervous system disorders Paraesthesia	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	4.5% 1/22 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Renal and urinary disorders Acute kidney injury	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	3.7% 1/27 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	4.5% 1/22 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Vascular disorders Haematoma	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	4.5% 1/22 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Gastrointestinal disorders Gastric ulcer	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	3.7% 1/27 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Gastrointestinal disorders Vomiting	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	3.7% 1/27 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	4.5% 1/22 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Nervous system disorders Depressed level of consciousness	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	3.7% 1/27 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Gastrointestinal disorders Diarrhoea	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	3.7% 1/27 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	18.2% 4/22 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Metabolism and nutrition disorders Dehydration	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	25.0% 2/8 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	11.1% 3/27 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	13.6% 3/22 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	3.7% 1/27 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	9.1% 2/22 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Metabolism and nutrition disorders Hypocalcaemia	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	4.5% 1/22 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Metabolism and nutrition disorders Hypomagnesaemia	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	4.5% 1/22 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Infections and infestations Arthritis infective	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	4.5% 1/22 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Infections and infestations Cystitis	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	4.5% 1/22 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Infections and infestations Osteomyelitis	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	4.5% 1/22 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Infections and infestations Soft tissue infection	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	4.5% 1/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	4.5% 1/22 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
General disorders Non-cardiac chest pain	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	3.7% 1/27 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Infections and infestations Urinary tract infection	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	3.7% 1/27 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Vascular disorders Hypertension	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	3.7% 1/27 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.

Other adverse events

Other adverse events
Measure	Phase 1 Neratinib 120mg; T-DM1 3.6mg/kg n=6 participants at risk Neratinib 120mg T-DM1 3.6mg/kg	Phase 1 Neratinib 160mg; T-DM1 3.6mg/kg n=10 participants at risk Neratinib 160mg T-DM1 3.6mg/kg	Phase 1 Neratinib 200mg; T-DM1 3.6mg/kg n=8 participants at risk Neratinib 200mg T-DM1 3.6mg/kg	Phase 1 Neratinib 240mg; T-DM1 3.6mg/kg n=3 participants at risk Neratinib 240mg T-DM1 3.6mg/kg	Neratinib and T-DM1 Part 1 (Phase 1) n=27 participants at risk Neratinib: Dose-Escalation Phase (Part 1) - Neratinib Dose-escalation will proceed on the basis of DLT during Cycle 1 starting at 120 mg/day. Dose level 1: 120 mg/day; Dose level 2: 160 mg/day; Dose level 3: 200 mg/day; Dose level 4: 240 mg/day T-DM1: Dose-Escalation Phase (Part 1) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.	Neratinib and T-DM1Part 1 (Phase 2) n=22 participants at risk Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy. Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.
Gastrointestinal disorders Dyspepsia	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	33.3% 1/3 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Gastrointestinal disorders Diarrhoea	100.0% 6/6 • Number of events 6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	90.0% 9/10 • Number of events 9 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	87.5% 7/8 • Number of events 7 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	100.0% 3/3 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	92.6% 25/27 • Number of events 25 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	86.4% 19/22 • Number of events 19 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Gastrointestinal disorders Nausea	100.0% 6/6 • Number of events 6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	60.0% 6/10 • Number of events 6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	37.5% 3/8 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	100.0% 3/3 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	66.7% 18/27 • Number of events 18 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	40.9% 9/22 • Number of events 9 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Gastrointestinal disorders Constipation	66.7% 4/6 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	40.0% 4/10 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	50.0% 4/8 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	44.4% 12/27 • Number of events 12 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	36.4% 8/22 • Number of events 8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Gastrointestinal disorders Vomiting	50.0% 3/6 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	50.0% 5/10 • Number of events 5 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	50.0% 4/8 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	33.3% 1/3 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	48.1% 13/27 • Number of events 13 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	31.8% 7/22 • Number of events 7 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Gastrointestinal disorders Dry mouth	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	20.0% 2/10 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	33.3% 1/3 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	18.5% 5/27 • Number of events 5 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	18.2% 4/22 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Gastrointestinal disorders Abdominal distension	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	33.3% 1/3 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	11.1% 3/27 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	9.1% 2/22 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Gastrointestinal disorders Stomatitis	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	9.1% 2/22 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Gastrointestinal disorders Abdominal pain	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	11.1% 3/27 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	18.2% 4/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Metabolism and nutrition disorders Hypokalaemia	50.0% 3/6 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	20.0% 2/10 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	62.5% 5/8 • Number of events 5 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	33.3% 1/3 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	40.7% 11/27 • Number of events 11 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	68.2% 15/22 • Number of events 15 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	60.0% 6/10 • Number of events 6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	50.0% 4/8 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	100.0% 3/3 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	48.1% 13/27 • Number of events 13 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Metabolism and nutrition disorders Hypoalbuminaemia	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	37.5% 3/8 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	18.5% 5/27 • Number of events 5 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	18.2% 4/22 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Metabolism and nutrition disorders Hyponatraemia	33.3% 2/6 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	25.0% 2/8 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	33.3% 1/3 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	22.2% 6/27 • Number of events 6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	18.2% 4/22 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Metabolism and nutrition disorders Dehydration	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	20.0% 2/10 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	62.5% 5/8 • Number of events 5 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	33.3% 1/3 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	33.3% 9/27 • Number of events 9 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	9.1% 2/22 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Metabolism and nutrition disorders Hypomagnesaemia	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	9.1% 2/22 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Investigations Aspartate aminotransferase increased	100.0% 6/6 • Number of events 6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	60.0% 6/10 • Number of events 6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	75.0% 6/8 • Number of events 6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	33.3% 1/3 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	70.4% 19/27 • Number of events 19 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	40.9% 9/22 • Number of events 9 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Investigations Platelet count decreased	83.3% 5/6 • Number of events 5 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	40.0% 4/10 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	50.0% 4/8 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	33.3% 1/3 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	51.9% 14/27 • Number of events 14 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	27.3% 6/22 • Number of events 6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Investigations Alanine aminotransferase increased	66.7% 4/6 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	50.0% 5/10 • Number of events 5 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	50.0% 4/8 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	48.1% 13/27 • Number of events 13 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	22.7% 5/22 • Number of events 5 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Investigations Weight decreased	50.0% 3/6 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	50.0% 5/10 • Number of events 5 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	75.0% 6/8 • Number of events 6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	51.9% 14/27 • Number of events 14 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	22.7% 5/22 • Number of events 5 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Investigations Blood creatinine increased	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	37.5% 3/8 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	14.8% 4/27 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	13.6% 3/22 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Investigations Blood bilirubin increased	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	9.1% 2/22 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
General disorders Fatigue	66.7% 4/6 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	50.0% 5/10 • Number of events 5 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	37.5% 3/8 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	66.7% 2/3 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	51.9% 14/27 • Number of events 14 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	54.5% 12/22 • Number of events 12 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
General disorders Pain	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	13.6% 3/22 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
General disorders Oedema peripheral	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	9.1% 2/22 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Nervous system disorders Peripheral sensory neuropathy	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	18.2% 4/22 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Nervous system disorders Dysgeusia	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	33.3% 1/3 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	14.8% 4/27 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	13.6% 3/22 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Nervous system disorders Headache	33.3% 2/6 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	25.0% 2/8 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	66.7% 2/3 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	25.9% 7/27 • Number of events 7 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	9.1% 2/22 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Musculoskeletal and connective tissue disorders Back pain	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	18.2% 4/22 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Musculoskeletal and connective tissue disorders Myalgia	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	33.3% 1/3 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	14.8% 4/27 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	9.1% 2/22 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Respiratory, thoracic and mediastinal disorders Epitaxis	33.3% 2/6 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	11.1% 3/27 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	9.1% 2/22 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Skin and subcutaneous tissue disorders Rash maculo-papular	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	13.6% 3/22 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Blood and lymphatic system disorders Anaemia	33.3% 2/6 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	20.0% 2/10 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	50.0% 4/8 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	29.6% 8/27 • Number of events 8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	22.7% 5/22 • Number of events 5 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Infections and infestations Upper respiratory tract infection	33.3% 2/6 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	9.1% 2/22 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Infections and infestations Urinary tract infection	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	20.0% 2/10 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	11.1% 3/27 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	9.1% 2/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Psychiatric disorders Insomnia	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	9.1% 2/22 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Vascular disorders Embolism	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/27 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	13.6% 3/22 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Gastrointestinal disorders Gastroesophageal reflux disease	33.3% 2/6 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Gastrointestinal disorders Abdominal pain upper	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	33.3% 1/3 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Investigations Lymphocyte count decreased	66.7% 4/6 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	30.0% 3/10 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	25.0% 2/8 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	33.3% 1/3 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	37.0% 10/27 • Number of events 10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Investigations Blood alkaline phosphatase increased	33.3% 2/6 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	50.0% 5/10 • Number of events 5 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	25.0% 2/8 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	33.3% 1/3 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	37.0% 10/27 • Number of events 10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Investigations Neutrophil count decreased	33.3% 2/6 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	20.0% 2/10 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	14.8% 4/27 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Investigations White blood cell count decreased	33.3% 2/6 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	14.8% 4/27 • Number of events 4 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Metabolism and nutrition disorders Hypocalcaemia	33.3% 2/6 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Metabolism and nutrition disorders Hypernatraemia	33.3% 2/6 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	25.0% 2/8 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	33.3% 1/3 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	22.2% 6/27 • Number of events 6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
General disorders Influenza like illness	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
General disorders Pyrexia	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Infections and infestations Lip infection	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	33.3% 1/3 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Infections and infestations Lung infection	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Infections and infestations Paronychia	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	25.0% 2/8 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	11.1% 3/27 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	20.0% 2/10 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Blood and lymphatic system disorders Leukopenia	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Respiratory, thoracic and mediastinal disorders Nasal congestion	33.3% 2/6 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	11.1% 3/27 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	33.3% 2/6 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	11.1% 3/27 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Respiratory, thoracic and mediastinal disorders Rhinitis allergic	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Respiratory, thoracic and mediastinal disorders Upper-airway cough syndrome	0.00% 0/6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Vascular disorders Hypertension	50.0% 3/6 • Number of events 3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	20.0% 2/10 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	22.2% 6/27 • Number of events 6 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Vascular disorders Hypotension	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Psychiatric disorders Confusional state	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	12.5% 1/8 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Psychiatric disorders Depression	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/10 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	33.3% 1/3 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Skin and subcutaneous tissue disorders Dermatitis acneiform	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.
Cardiac disorders Sinus tachycardia	16.7% 1/6 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	10.0% 1/10 • Number of events 1 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/8 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/3 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	7.4% 2/27 • Number of events 2 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.	0.00% 0/22 • From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.

Additional Information

Judy Langer, Director of Regulatory Affairs

NSABP Foundation, Inc.

Phone: 412-339-5300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60