Trial Outcomes & Findings for Doxycycline, Temozolomide and Ipilimumab in Melanoma (NCT NCT01590082)

Last Updated: 2020-09-02

Results Overview

Number of participants with response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Complete Response (CR): Disappearance all target lesions; Any pathological lymph nodes must be \<10mm in short axis. Partial Response (PR): \>30% decrease in sum of diameters of target lesions, reference baseline sum of diameters (e.g. percent change from baseline). Stable Disease (SD): Neither sufficient shrinkage for PR nor sufficient increase for progressive disease. Progressive Disease (PD): \>20% increase in sum of diameters of target lesions, reference smallest sum of diameters recorded since treatment started (e.g. percent change from nadir, where nadir defined as smallest sum of diameters recorded since treatment start). In addition, sum must have an absolute increase from nadir of 5mm. Not Applicable (NA): No target lesions at baseline. Not Evaluable (NE): Cannot be classified by 1 of 5 preceding definitions.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

12 participants

Primary outcome timeframe

2 cycles, up to 7 weeks

Results posted on

2020-09-02

Participant Flow

Recruitment period: November 6, 2012 to March 30, 2015. All recruitment done at The University of Texas MD Anderson Cancer Center.

Participant milestones

Participant milestones
Measure	Phase I: Doxycycline + Ipilimumab + Temozolomide Oral Doxycycline starting dose 200 mg twice a day on Day -6 of Cycle 1 (1 week before Day 1 of Cycle 1 starts), thereafter with Ipilimumab 3 mg by vein (IV) on Day 1 of each 21 day cycle for 4 cycles, oral Temozolomide 200 mg/m2 on Days 1 - 4 of each 21 day cycle for 4 cycles.	Phase II Oral Doxycycline 200 mg twice a day on Day -6 of Cycle 1 (1 week before Day 1 of Cycle 1 starts), thereafter with Ipilimumab 3 mg by vein (IV) on Day 1 of each 21 day cycle for 4 cycles, oral Temozolomide 200 mg/m2 on Days 1 - 4 of each 21 day cycle for 4 cycles.
Overall Study STARTED	11	1
Overall Study COMPLETED	9	1
Overall Study NOT COMPLETED	2	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase I: Doxycycline + Ipilimumab + Temozolomide Oral Doxycycline starting dose 200 mg twice a day on Day -6 of Cycle 1 (1 week before Day 1 of Cycle 1 starts), thereafter with Ipilimumab 3 mg by vein (IV) on Day 1 of each 21 day cycle for 4 cycles, oral Temozolomide 200 mg/m2 on Days 1 - 4 of each 21 day cycle for 4 cycles.	Phase II Oral Doxycycline 200 mg twice a day on Day -6 of Cycle 1 (1 week before Day 1 of Cycle 1 starts), thereafter with Ipilimumab 3 mg by vein (IV) on Day 1 of each 21 day cycle for 4 cycles, oral Temozolomide 200 mg/m2 on Days 1 - 4 of each 21 day cycle for 4 cycles.
Overall Study Withdrawal by Subject	1	0
Overall Study Ineligible	1	0

Baseline Characteristics

Doxycycline, Temozolomide and Ipilimumab in Melanoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I: Doxycycline + Ipilimumab + Temozolomide n=11 Participants Oral Doxycycline starting dose 200 mg twice a day on Day -6 of Cycle 1 (1 week before Day 1 of Cycle 1 starts), thereafter with Ipilimumab 3 mg by vein (IV) on Day 1 of each 21 day cycle for 4 cycles, oral Temozolomide 200 mg/m2 on Days 1 - 4 of each 21 day cycle for 4 cycles.	Phase II n=1 Participants Oral Doxycycline 200 mg twice a day on Day -6 of Cycle 1 (1 week before Day 1 of Cycle 1 starts), thereafter with Ipilimumab 3 mg by vein (IV) on Day 1 of each 21 day cycle for 4 cycles, oral Temozolomide 200 mg/m2 on Days 1 - 4 of each 21 day cycle for 4 cycles.	Total n=12 Participants Total of all reporting groups
Age, Continuous	66 years n=5 Participants	84 years n=7 Participants	67 years n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	1 Participants n=7 Participants	9 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	11 Participants n=5 Participants	0 Participants n=7 Participants	11 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 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
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	11 Participants n=5 Participants	1 Participants n=7 Participants	12 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	11 participants n=5 Participants	1 participants n=7 Participants	12 participants n=5 Participants

PRIMARY outcome

Timeframe: 2 cycles, up to 7 weeks

Population: Due to early termination participants did not move to Phase 2 and no data collected.

Outcome measures

Outcome measures
Measure	Phase I: Doxycycline, Ipilimumab, and Temozolomide n=10 Participants Oral Doxycycline starting dose 200 mg twice a day on Day -6 of Cycle 1 (1 week before Day 1 of Cycle 1 starts), thereafter with Ipilimumab 3 mg by vein (IV) on Day 1 of each 21 day cycle for 4 cycles, oral Temozolomide 200 mg/m2 on Days 1 - 4 of each 21 day cycle for 4 cycles.	Phase II Oral Doxycycline 200 mg twice a day on Day -6 of Cycle 1 (1 week before Day 1 of Cycle 1 starts), thereafter with Ipilimumab 3 mg by vein (IV) on Day 1 of each 21 day cycle for 4 cycles, oral Temozolomide 200 mg/m2 on Days 1 - 4 of each 21 day cycle for 4 cycles.
Overall Participant Response Complete Response (CR)	0 Participants	—
Overall Participant Response Partial Response (PR)	0 Participants	—
Overall Participant Response Stable Disease (SD)	3 Participants	—
Overall Participant Response Progressive Disease (PD)	6 Participants	—
Overall Participant Response Not Evaluable (NE)	1 Participants	—

Adverse Events

Phase I: Doxycycline + Ipilimumab + Temozolomide

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Phase II

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Sapna P. Patel, Associate Professor, Melanoma Medical Oncology

The University of Texas (UT) MD Anderson Cancer Center

Phone: (713) 792-2921

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Other adverse events
Measure	Phase I: Doxycycline + Ipilimumab + Temozolomide n=9 participants at risk Oral Doxycycline starting dose 200 mg twice a day on Day -6 of Cycle 1 (1 week before Day 1 of Cycle 1 starts), thereafter with Ipilimumab 3 mg by vein (IV) on Day 1 of each 21 day cycle for 4 cycles, oral Temozolomide 200 mg/m2 on Days 1 - 4 of each 21 day cycle for 4 cycles.	Phase II n=1 participants at risk Oral Doxycycline 200 mg twice a day on Day -6 of Cycle 1 (1 week before Day 1 of Cycle 1 starts), thereafter with Ipilimumab 3 mg by vein (IV) on Day 1 of each 21 day cycle for 4 cycles, oral Temozolomide 200 mg/m2 on Days 1 - 4 of each 21 day cycle for 4 cycles.
General disorders Abdominal pain	33.3% 3/9 • Number of events 4 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Investigations Activated partial thromboplastin time prolonged	0.00% 0/9 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	100.0% 1/1 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Investigations Alanine aminotransferase increased	33.3% 3/9 • Number of events 3 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Blood and lymphatic system disorders Anemia	55.6% 5/9 • Number of events 6 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Metabolism and nutrition disorders Anorexia	77.8% 7/9 • Number of events 12 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	100.0% 1/1 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Musculoskeletal and connective tissue disorders Arthralgia	44.4% 4/9 • Number of events 4 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Investigations Aspartate aminotransferase increased	55.6% 5/9 • Number of events 5 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	100.0% 1/1 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Cardiac disorders Atrial fibrillation	0.00% 0/9 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	100.0% 1/1 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Gastrointestinal disorders Bloating	22.2% 2/9 • Number of events 3 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Investigations Blood bilirubin increased	0.00% 0/9 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	100.0% 1/1 • Number of events 2 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Eye disorders Blurred vision	33.3% 3/9 • Number of events 3 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Cardiac disorders Chest pain - cardiac	11.1% 1/9 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
General disorders Chills	22.2% 2/9 • Number of events 2 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Psychiatric disorders Confusion	11.1% 1/9 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Gastrointestinal disorders Constipation	33.3% 3/9 • Number of events 6 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	100.0% 1/1 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Respiratory, thoracic and mediastinal disorders Cough	33.3% 3/9 • Number of events 3 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	100.0% 1/1 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Investigations Creatinine increased	22.2% 2/9 • Number of events 2 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Psychiatric disorders Depression	11.1% 1/9 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Gastrointestinal disorders Diarrhea	33.3% 3/9 • Number of events 7 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	100.0% 1/1 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Nervous system disorders Dizziness	55.6% 5/9 • Number of events 7 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Gastrointestinal disorders Dry mouth	11.1% 1/9 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Skin and subcutaneous tissue disorders Dry skin	55.6% 5/9 • Number of events 5 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Respiratory, thoracic and mediastinal disorders Dyspnea	22.2% 2/9 • Number of events 2 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	100.0% 1/1 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Ear and labyrinth disorders Ear pain	11.1% 1/9 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Musculoskeletal and connective tissue disorders Edema limbs	66.7% 6/9 • Number of events 10 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Endocrine disorders Endocrine disorders - (Other	22.2% 2/9 • Number of events 2 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
General disorders Fatigue	77.8% 7/9 • Number of events 13 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	100.0% 1/1 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
General disorders Fever	11.1% 1/9 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
General disorders Flu like symptoms	11.1% 1/9 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Vascular disorders Flushing	22.2% 2/9 • Number of events 2 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	33.3% 3/9 • Number of events 5 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Nervous system disorders Headache	66.7% 6/9 • Number of events 6 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Metabolism and nutrition disorders Hyperglycemia	11.1% 1/9 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Metabolism and nutrition disorders Hyperkalemia	22.2% 2/9 • Number of events 3 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Metabolism and nutrition disorders Hypermagnesemia	11.1% 1/9 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Metabolism and nutrition disorders Hypomagnesemia	22.2% 2/9 • Number of events 3 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Metabolism and nutrition disorders Hyponatremia	11.1% 1/9 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Infections and infestations Infections and infestations - (Other)	0.00% 0/9 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	100.0% 1/1 • Number of events 2 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Investigations INR increased	0.00% 0/9 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	100.0% 1/1 • Number of events 1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.
Psychiatric disorders Insomnia	33.3% 3/9 • Number of events 4 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.	0.00% 0/1 • Adverse event evaluation Phase I: Patients will be evaluated at baseline (and/or day -6) and on days 1, 8 and 15 during cycle 1, and then on day 1 every cycle. Phase II: Patients will be evaluated ate baseline (and/or day -6) and on day 1 during cycle 1, and then on day 1 every cycle. Collection up to Cycle 5, approximately 15 weeks.