Trial Outcomes & Findings for Phase I/II Trial of Tivantinib With FOLFOX for the Treatment of Advanced Solid Tumors and Previously Untreated Metastatic Adenocarcinoma of the Distal Esophagus, Gastroesophageal Junction or Stomach (NCT NCT01611857)

Last Updated: 2016-11-23

Results Overview

Using a standard 3+3 design participants were enrolled in dose-escalating cohorts to determine the maximum tolerated dose (MTD) of tivantinib when given with FOLFOX (5-FU 400 mg/m\^2, continuous IV 5-FU 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2). MTD is defined as the highest dose level at which no more than 1 of 6 patients experiences a DLT, assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

49 participants

Primary outcome timeframe

14 Days (1 cycle)

Results posted on

2016-11-23

Participant Flow

Between January 2012 and March 2014, 49 patients were enrolled at multiple centers in the U.S. Fifteen patients with advanced solid tumors were enrolled in the dose escalation phase, and 34 patients with first-line metastatic cancer of the esophagus, gastroesophageal (GE) junction, or stomach in the expansion phase.

Forty-nine patients were enrolled; 47 were treated. Two participants withdrew prior to dosing. 15 participants were enrolled and treated in the dose escalation phase. 34 participants were enrolled in the dose expansion phase; however only 32 were treated. Patients continued treatment until disease progression or intolerable toxicity.

Participant milestones

Participant milestones
Measure	Tivantinib + FOLFOX Dose Escalation Tivantinib: (120 mg; 240 mg; or 360 mg) orally, twice daily (PO BID) on Days 1-14 of each 2 week cycle; FOLFOX: \[5-Fluorouracil (5-FU) 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2\] on Day 1 each cycle.	Tivantinib + FOLFOX Dose Expansion Tivantinib: 360 mg PO BID on Days 1-14 of each 2-week cycle. FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 of each 2-week cycle.
Overall Study STARTED	15	34
Overall Study Tivantinib 120 mg	5	0
Overall Study Tivantinib 240 mg	3	0
Overall Study Tivantinib 360 mg	7	32
Overall Study COMPLETED	15	32
Overall Study NOT COMPLETED	0	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Tivantinib + FOLFOX Dose Escalation Tivantinib: (120 mg; 240 mg; or 360 mg) orally, twice daily (PO BID) on Days 1-14 of each 2 week cycle; FOLFOX: \[5-Fluorouracil (5-FU) 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2\] on Day 1 each cycle.	Tivantinib + FOLFOX Dose Expansion Tivantinib: 360 mg PO BID on Days 1-14 of each 2-week cycle. FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 of each 2-week cycle.
Overall Study Withdrawal by Subject	0	2

Baseline Characteristics

Phase I/II Trial of Tivantinib With FOLFOX for the Treatment of Advanced Solid Tumors and Previously Untreated Metastatic Adenocarcinoma of the Distal Esophagus, Gastroesophageal Junction or Stomach

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tivantinib+FOLFOX Dose Escalation n=15 Participants Tivantinib: (120 mg, 240 mg, or 360 mg) orally, twice daily on Days 1-14 of each 2 week cycle. FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 each cycle.	Tivantinib+FOLFOX Dose Expansion n=34 Participants Tivantinib: 360 mg PO BID on Days 1-14 of each 2-week cycle; FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 of each 2-week cycle. Treatment continued until disease progression or unacceptable toxicity.	Total n=49 Participants Total of all reporting groups
Age, Continuous	62 years n=5 Participants	65 years n=7 Participants	63.5 years n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	8 Participants n=7 Participants	13 Participants n=5 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	26 Participants n=7 Participants	36 Participants n=5 Participants
Region of Enrollment United States	15 participants n=5 Participants	34 participants n=7 Participants	49 participants n=5 Participants
Tumor Type Colorectal	7 participants n=5 Participants	0 participants n=7 Participants	7 participants n=5 Participants
Tumor Type Esophageal	4 participants n=5 Participants	14 participants n=7 Participants	18 participants n=5 Participants
Tumor Type Pancreatic	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Tumor Type GE Junction	1 participants n=5 Participants	9 participants n=7 Participants	10 participants n=5 Participants
Tumor Type Cholangiocarcinoma	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Tumor Type Unknown primary	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Tumor Type Gastric	0 participants n=5 Participants	11 participants n=7 Participants	11 participants n=5 Participants
Karnofsky Performance Score 100	2 participants n=5 Participants	7 participants n=7 Participants	9 participants n=5 Participants
Karnofsky Performance Score 90	3 participants n=5 Participants	18 participants n=7 Participants	21 participants n=5 Participants
Karnofsky Performance Score 80	10 participants n=5 Participants	3 participants n=7 Participants	13 participants n=5 Participants
Karnofsky Performance Score 70	0 participants n=5 Participants	5 participants n=7 Participants	5 participants n=5 Participants
Karnofsky Performance Score 60	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Karnofsky Performance Score 50	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Karnofsky Performance Score 40	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Karnofsky Performance Score 30	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Karnofsky Performance Score 20	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Karnofsky Performance Score 10	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Karnofsky Performance Score 0	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Karnofsky Performance Score Unknown	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Number of Participants with Prior Radiation Therapy Received Prior Radiation: Yes	5 participants n=5 Participants	11 participants n=7 Participants	16 participants n=5 Participants
Number of Participants with Prior Radiation Therapy Received Prior Radiation: No	10 participants n=5 Participants	23 participants n=7 Participants	33 participants n=5 Participants

PRIMARY outcome

Timeframe: 14 Days (1 cycle)

Population: Patients were assessed for DLT if they received at least 85% of the scheduled doses of study drugs in cycle 1. In the Tivantinib 120 mg cohort two participants were replaced due to missed drug. In the Tivantinib 360 mg cohort one patient was replaced due to an allergic reaction to oxaliplatin.

Outcome measures

Outcome measures
Measure	Tivantinib 120 mg (PO BID) + FOLFOX n=3 Participants Tivantinib 120 mg given orally, twice daily (PO BID) on Days 1-14 of each 14-day cycle; FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 each cycle.	Tivantinib 240 mg (PO BID) + FOLFOX n=3 Participants Tivantinib 240 mg given orally, twice daily (PO BID) on Days 1-14 of each 14-day cycle; FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 each cycle.	Tivantinib 360 mg (PO BID) + FOLFOX n=6 Participants Tivantinib 360 mg given orally, twice daily (PO BID) on Days 1-14 of each 14-day cycle cycle; FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 each cycle.
The Incidence of Dose Limiting Toxicities (DLT) in Phase I Dose Escalation	0 participants	0 participants	1 participants

SECONDARY outcome

Timeframe: every 8 weeks until treatment discontinuation, projected 18 months and then every 3 months thereafter up to 5 years from start of treatment.

Population: The analysis was performed on an Intent-to-Treat basis (N = 34) for all participants in the Phase II portion of the study. Median follow-up was 15 months (3-21 months)

Defined as the time from first treatment until objective tumor progression or death from any cause. 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	Tivantinib 120 mg (PO BID) + FOLFOX n=34 Participants Tivantinib 120 mg given orally, twice daily (PO BID) on Days 1-14 of each 14-day cycle; FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 each cycle.	Tivantinib 240 mg (PO BID) + FOLFOX Tivantinib 240 mg given orally, twice daily (PO BID) on Days 1-14 of each 14-day cycle; FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 each cycle.	Tivantinib 360 mg (PO BID) + FOLFOX Tivantinib 360 mg given orally, twice daily (PO BID) on Days 1-14 of each 14-day cycle cycle; FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 each cycle.
Progression Free Survival in Phase II Dose Expansion	6.1 months Interval 3.6 to 7.8	—	—

SECONDARY outcome

Timeframe: every 8 weeks until treatment discontinuation, an expected average of 18 months, then every 12 weeks thereafter up to 5 years from start of treatment.

Population: The analysis was performed on an Intent-to-Treat basis (N=34) for all participants in the Phase II portion of the study.

Defined as the time from first treatment until death from any cause.

Outcome measures

Outcome measures
Measure	Tivantinib 120 mg (PO BID) + FOLFOX n=34 Participants Tivantinib 120 mg given orally, twice daily (PO BID) on Days 1-14 of each 14-day cycle; FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 each cycle.	Tivantinib 240 mg (PO BID) + FOLFOX Tivantinib 240 mg given orally, twice daily (PO BID) on Days 1-14 of each 14-day cycle; FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 each cycle.	Tivantinib 360 mg (PO BID) + FOLFOX Tivantinib 360 mg given orally, twice daily (PO BID) on Days 1-14 of each 14-day cycle cycle; FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 each cycle.
Overall Survival in Phase II Dose Expansion	9.6 months Interval 7.2 to The upper limit of the 95% Confidence Interval had not been reached at the time of analysis.	—	—

SECONDARY outcome

Timeframe: every 8 weeks until progressive disease, expected 18 months.

Population: The analysis was performed on all participants (N = 34) in the Phase II portion of the study.

Defined as the time from first treatment until objective tumor progression. 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	Tivantinib 120 mg (PO BID) + FOLFOX n=34 Participants Tivantinib 120 mg given orally, twice daily (PO BID) on Days 1-14 of each 14-day cycle; FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 each cycle.	Tivantinib 240 mg (PO BID) + FOLFOX Tivantinib 240 mg given orally, twice daily (PO BID) on Days 1-14 of each 14-day cycle; FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 each cycle.	Tivantinib 360 mg (PO BID) + FOLFOX Tivantinib 360 mg given orally, twice daily (PO BID) on Days 1-14 of each 14-day cycle cycle; FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 each cycle.
Time to Progression in Phase II Dose Expansion	7.0 months Interval 5.7 to 11.5	—	—

Adverse Events

Tivantinib+FOLFOX Dose Escalation

Serious events: 6 serious events

Other events: 14 other events

Deaths: 0 deaths

Tivantinib+FOLFOX Dose Expansion

Serious events: 17 serious events

Other events: 31 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Charles H. Davis

Sarah Cannon Research Institute

Phone: 615-524-4341

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The sponsor can review/embargo results communications prior to public release for a period that is \>60 days but ≤180 days from date submitted to sponsor, who may require changes to the communication in order to remove specifically identified confidential information (other than study data) and/or delay the proposed publication to enable the sponsor to seek patent protection for inventions. The PI may not publish its results until 18 mos. after the trial has been completed at all sites.
Publication restrictions are in place

Restriction type: OTHER

Measure	Tivantinib+FOLFOX Dose Escalation n=15 participants at risk Tivantinib: orally, twice daily (PO BID) on Days 1-14 of each 2 week cycle; FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 each cycle.	Tivantinib+FOLFOX Dose Expansion n=32 participants at risk Tivantinib: 360 mg PO BID on Days 1-14 of each 2-week cycle. FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 of each 2-week cycle. Treatment continued until disease progression or unacceptable toxicity.
Gastrointestinal disorders Vomiting	20.0% 3/15 • Number of events 3 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Gastrointestinal disorders Diarhhea	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	6.2% 2/32 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Infections and infestations Sepsis	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Blood and lymphatic system disorders Anemia	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Blood and lymphatic system disorders Neutropenia	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Blood and lymphatic system disorders Febrile neutropenia	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Gastrointestinal disorders Abdominal pain	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Nervous system disorders Encephalopathy	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Respiratory, thoracic and mediastinal disorders Respiratory failure	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Cardiac disorders Myocardial infarction	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Eye disorders Optic nerve disorder	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Infections and infestations Bacteremia	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Gastrointestinal disorders Nausea	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
General disorders Asthenia	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Gastrointestinal disorders Ileus	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Vascular disorders Embolism	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Metabolism and nutrition disorders Hyperglycemia	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Infections and infestations Pneumonia	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Nervous system disorders Cerebrovascular accident	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Nervous system disorders Ischemic stroke	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Respiratory, thoracic and mediastinal disorders Respiratory arrest	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Infections and infestations Septic shock	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
General disorders Non-cardiac chest pain	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.

Measure	Tivantinib+FOLFOX Dose Escalation n=15 participants at risk Tivantinib: orally, twice daily (PO BID) on Days 1-14 of each 2 week cycle; FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 each cycle.	Tivantinib+FOLFOX Dose Expansion n=32 participants at risk Tivantinib: 360 mg PO BID on Days 1-14 of each 2-week cycle. FOLFOX: (5-FU 400 mg/m\^2, 5-FU continuous IV 2400 mg/m\^2 over 46 hours, leucovorin 400 mg/m\^2 IV, and oxaliplatin 85 mg/m\^2) on Day 1 of each 2-week cycle. Treatment continued until disease progression or unacceptable toxicity.
Blood and lymphatic system disorders Neutropenia	26.7% 4/15 • Number of events 7 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	62.5% 20/32 • Number of events 20 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
General disorders Fatigue	53.3% 8/15 • Number of events 10 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	56.2% 18/32 • Number of events 18 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Gastrointestinal disorders Nausea	46.7% 7/15 • Number of events 8 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	50.0% 16/32 • Number of events 16 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Gastrointestinal disorders Diarrhea	33.3% 5/15 • Number of events 6 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	50.0% 16/32 • Number of events 16 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Nervous system disorders Peripheral neuropathy	33.3% 5/15 • Number of events 10 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	43.8% 14/32 • Number of events 14 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
General disorders Temperature intolerance	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	31.2% 10/32 • Number of events 10 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
General disorders Mucositis	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	28.1% 9/32 • Number of events 9 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Blood and lymphatic system disorders Thrombocytopenia	40.0% 6/15 • Number of events 14 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	28.1% 9/32 • Number of events 9 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Blood and lymphatic system disorders Anemia	33.3% 5/15 • Number of events 14 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	25.0% 8/32 • Number of events 8 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Gastrointestinal disorders Constipation	33.3% 5/15 • Number of events 5 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	25.0% 8/32 • Number of events 8 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Gastrointestinal disorders Vomiting	20.0% 3/15 • Number of events 5 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	25.0% 8/32 • Number of events 8 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Metabolism and nutrition disorders Anorexia	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	18.8% 6/32 • Number of events 6 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Nervous system disorders Dizziness	13.3% 2/15 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	15.6% 5/32 • Number of events 5 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	12.5% 4/32 • Number of events 4 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Skin and subcutaneous tissue disorders Alopecia	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	9.4% 3/32 • Number of events 3 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
General disorders Asthenia	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	9.4% 3/32 • Number of events 3 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Cardiac disorders Bradycardia	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	9.4% 3/32 • Number of events 3 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	9.4% 3/32 • Number of events 3 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Investigations Weight decreased	13.3% 2/15 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	9.4% 3/32 • Number of events 3 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Infections and infestations Candida infection	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	6.2% 2/32 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
General disorders Chills	13.3% 2/15 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	6.2% 2/32 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Skin and subcutaneous tissue disorders Dry skin	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	6.2% 2/32 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Nervous system disorders Dysgeusia	13.3% 2/15 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	6.2% 2/32 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Gastrointestinal disorders Dyspepsia	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	6.2% 2/32 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
General disorders Edema	6.7% 1/15 • Number of events 3 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	6.2% 2/32 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	6.2% 2/32 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Respiratory, thoracic and mediastinal disorders Hiccups	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	6.2% 2/32 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Blood and lymphatic system disorders Leukopenia	20.0% 3/15 • Number of events 3 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	6.2% 2/32 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Musculoskeletal and connective tissue disorders Myalgia	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	6.2% 2/32 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Gastrointestinal disorders Oral pain	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	6.2% 2/32 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Nervous system disorders Paresthesia	6.7% 1/15 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	6.2% 2/32 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
General disorders Pyrexia	13.3% 2/15 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	6.2% 2/32 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Eye disorders Visual impairment	0.00% 0/15 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	6.2% 2/32 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Nervous system disorders Headache	6.7% 1/15 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Blood and lymphatic system disorders Blood bilirubin increased	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Investigations QT prolongation	20.0% 3/15 • Number of events 6 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	6.2% 2/32 • Number of events 5 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Gastrointestinal disorders Proctolgia	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Skin and subcutaneous tissue disorders Erythema	13.3% 2/15 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Skin and subcutaneous tissue disorders Pruritus	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Investigations Aspartate aminotransferase increased	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Investigations Alkaline phosphatase increased	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Investigations Alanine aminotransferase increased	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	13.3% 2/15 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	6.2% 2/32 • Number of events 3 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Skin and subcutaneous tissue disorders Maculo-papular rash	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Metabolism and nutrition disorders Dehydration	13.3% 2/15 • Number of events 3 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	3.1% 1/32 • Number of events 2 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Gastrointestinal disorders Stomatitis	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	9.4% 3/32 • Number of events 4 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Skin and subcutaneous tissue disorders Erythematous rash	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Skin and subcutaneous tissue disorders Photosensitivity	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Gastrointestinal disorders Muscosal inflammation	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	18.8% 6/32 • Number of events 7 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Nervous system disorders Somnolence	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
General disorders Peripheral edema	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Psychiatric disorders Libido decreased	6.7% 1/15 • Number of events 1 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.	0.00% 0/32 • Collected from day of first dose to 30 days after last dose of study medication up to 18 months.