Trial Outcomes & Findings for Enzastaurin in Combination of Capecitabine to Treat Breast Cancer (NCT NCT00437294)

Last Updated: 2020-08-10

Results Overview

PFS was defined as the time from randomization to the first observation of disease progression or death due to any cause. For participants not known to have died as of the data cut-off date and who did not have progressive disease, PFS was censored at the date of last visit with adequate assessment. For participants who received subsequent anticancer therapy (after discontinuation from the study treatment) prior to disease progression or death, PFS was censored at the date of last visit with adequate assessment prior to the initiation of post-discontinuation anticancer therapy.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

86 participants

Primary outcome timeframe

Randomization to measured progressive disease or death up to 14 months

Results posted on

2020-08-10

Participant Flow

Participant flow reports those participants who discontinued from study drug.

Participant milestones

Participant milestones
Measure	Capecitabine + Enzastaurin Capecitabine: 1250 milligrams per square meter (mg/m\^2), twice daily (BID) on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Enzastaurin: 1125-milligram (mg) loading dose on Day 1 of Cycle 1, then 500 mg daily on subsequent days to complete 21-day cycles until progressive disease.	Capecitabine + Placebo Capecitabine: 1250 mg/m\^2, BID on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Placebo: taken as 4 tablets orally, daily, to complete 21-day cycles until progressive disease.
Overall Study STARTED	43	43
Overall Study Received at Least 1 Dose of Study Drug	42	43
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	43	43

Reasons for withdrawal

Reasons for withdrawal
Measure	Capecitabine + Enzastaurin Capecitabine: 1250 milligrams per square meter (mg/m\^2), twice daily (BID) on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Enzastaurin: 1125-milligram (mg) loading dose on Day 1 of Cycle 1, then 500 mg daily on subsequent days to complete 21-day cycles until progressive disease.	Capecitabine + Placebo Capecitabine: 1250 mg/m\^2, BID on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Placebo: taken as 4 tablets orally, daily, to complete 21-day cycles until progressive disease.
Overall Study Adverse Event	5	4
Overall Study Death	5	2
Overall Study Physician Decision	0	3
Overall Study Withdrawal by Subject	5	0
Overall Study Progressive Disease	19	23
Overall Study Sponsor Decision	8	9
Overall Study Protocol Violation	0	1
Overall Study Entry criteria not met	1	1

Baseline Characteristics

Enzastaurin in Combination of Capecitabine to Treat Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Capecitabine + Enzastaurin n=42 Participants Capecitabine: 1250 milligrams per square meter (mg/m\^2), twice daily (BID) on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Enzastaurin: 1125-milligram (mg) loading dose on Day 1 of Cycle 1, then 500 mg daily on subsequent days to complete 21-day cycles until progressive disease.	Capecitabine + Placebo n=43 Participants Capecitabine: 1250 mg/m\^2, BID on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycles until progressive disease. Placebo: taken as 4 tablets orally, tablets daily, to complete 21-day cycles until progressive disease.	Total n=85 Participants Total of all reporting groups
Age, Continuous	55.73 years STANDARD_DEVIATION 10.06 • n=5 Participants	52.14 years STANDARD_DEVIATION 9.78 • n=7 Participants	53.91 years STANDARD_DEVIATION 10.02 • n=5 Participants
Sex: Female, Male Female	42 Participants n=5 Participants	43 Participants n=7 Participants	85 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants n=5 Participants	5 Participants n=7 Participants	11 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	36 Participants n=5 Participants	38 Participants n=7 Participants	74 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/Ethnicity, Customized White	31 Participants n=5 Participants	31 Participants n=7 Participants	62 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Asian	2 Participants n=5 Participants	7 Participants n=7 Participants	9 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic	6 Participants n=5 Participants	5 Participants n=7 Participants	11 Participants n=5 Participants
Region of Enrollment South Africa	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Region of Enrollment Mexico	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Region of Enrollment Argentina	9 Participants n=5 Participants	7 Participants n=7 Participants	16 Participants n=5 Participants
Region of Enrollment Australia	11 Participants n=5 Participants	11 Participants n=7 Participants	22 Participants n=5 Participants
Region of Enrollment Canada	16 Participants n=5 Participants	18 Participants n=7 Participants	34 Participants n=5 Participants
Body Mass Index (BMI)	27.25 kilograms per square meter (kg/m^2) STANDARD_DEVIATION 6.48 • n=5 Participants	27.04 kilograms per square meter (kg/m^2) STANDARD_DEVIATION 4.95 • n=7 Participants	27.14 kilograms per square meter (kg/m^2) STANDARD_DEVIATION 5.73 • n=5 Participants
Body Surface Area (BSA)	1.73 square meter (m^2) STANDARD_DEVIATION 0.20 • n=5 Participants	1.76 square meter (m^2) STANDARD_DEVIATION 0.20 • n=7 Participants	1.75 square meter (m^2) STANDARD_DEVIATION 0.20 • n=5 Participants
Disease Stage Stage I	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Disease Stage Stage II	5 Participants n=5 Participants	10 Participants n=7 Participants	15 Participants n=5 Participants
Disease Stage Stage IIA	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Disease Stage Stage IIB	6 Participants n=5 Participants	7 Participants n=7 Participants	13 Participants n=5 Participants
Disease Stage Stage III	2 Participants n=5 Participants	5 Participants n=7 Participants	7 Participants n=5 Participants
Disease Stage Stage IIIA	10 Participants n=5 Participants	1 Participants n=7 Participants	11 Participants n=5 Participants
Disease Stage Stage IIIB	7 Participants n=5 Participants	3 Participants n=7 Participants	10 Participants n=5 Participants
Disease Stage Stage IIIC	2 Participants n=5 Participants	7 Participants n=7 Participants	9 Participants n=5 Participants
Disease Stage Stage IV	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Disease Stage Stage IVB	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization to measured progressive disease or death up to 14 months

Population: Intent-to-treat (ITT) population: All randomized participants who received at least 1 dose of study drug. Participants censored: Capecitabine + Enzastaurin = 13; Capecitabine + Placebo = 14.

Outcome measures

Outcome measures
Measure	Capecitabine + Enzastaurin n=42 Participants Capecitabine: 1250 milligrams per square meter (mg/m\^2), twice daily (BID) on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Enzastaurin: 1125 1125-milligram (mg) loading dose on Day 1 of Cycle 1, then 500 mg daily on subsequent days to complete 21-day cycles until progressive disease.	Capecitabine + Placebo n=43 Participants Capecitabine: 1250 mg/m\^2, BID on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Placebo: taken as 4 tablets orally, daily, to complete 21-day cycles until progressive disease.
Progression Free Survival (PFS)	2.79 months Interval 2.1 to 4.63	4.27 months Interval 2.89 to 6.18

SECONDARY outcome

Timeframe: Randomization, Cycle 2, end of study

Population: Zero participants were analyzed. The study was terminated and no data was collected.

Protein expression was planned to be measured using an Immunohistochemistry (IHC) assay to determine membrane and cytoplasmic phosphorylated glycogen synthase kinase 3 beta (pGSK3B), nuclear phosphorylated adenosine 3'5'-cyclic monophosphate (cAMP) response-element binding protein (pCREB), cytoplasmic pCREB, protein kinase C beta 2 (PKCB2), cytoplasmic phospho S6 (pS6), and cytoplasmic phosphatase and tensin homolog (PTEN) IHC H-scores. Tumor tissue samples were to be scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system for cytoplasmic and nuclear staining, and H- scores calculated using formula: 1x(percentage of cells stained 1+) + 2x(percentage of cells stained 2+) + 3x(percentage of cells stained 3+) .

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From pre-dose to 24 hours post-dose on Day 1 of Cycle 2

Population: All randomized participants who received at least 1 dose of enzastaurin and had data for AUCτ,ss analysis.

Area Under the Concentration versus time curve during 1 dosing interval at steady state (AUCτ,ss) for Cycle 2 Day 1 for Enzastaurin, its metabolite LY326020 and total analytes (enzastaurin + LY326020). AUCτ,ss was calculated using concentration versus time data by post hoc estimation of enzastaurin, its metabolite LY326020, and total analytes (enzastaurin + LY326020).

Outcome measures

Outcome measures
Measure	Capecitabine + Enzastaurin n=11 Participants Capecitabine: 1250 milligrams per square meter (mg/m\^2), twice daily (BID) on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Enzastaurin: 1125 1125-milligram (mg) loading dose on Day 1 of Cycle 1, then 500 mg daily on subsequent days to complete 21-day cycles until progressive disease.	Capecitabine + Placebo Capecitabine: 1250 mg/m\^2, BID on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Placebo: taken as 4 tablets orally, daily, to complete 21-day cycles until progressive disease.
Pharmacokinetics: Area Under the Concentration Versus Time Curve During One Dosing Interval at Steady State Enzastaurin	90000 nanomoleshour per liter (nmolhr/L) Geometric Coefficient of Variation 99	—
Pharmacokinetics: Area Under the Concentration Versus Time Curve During One Dosing Interval at Steady State Enzastaurin Metabolite LY326020	40700 nanomoleshour per liter (nmolhr/L) Geometric Coefficient of Variation 31	—
Pharmacokinetics: Area Under the Concentration Versus Time Curve During One Dosing Interval at Steady State Total Analytes (enzastaurin + LY326020)	137000 nanomoleshour per liter (nmolhr/L) Geometric Coefficient of Variation 66	—

SECONDARY outcome

Timeframe: Pre-dose to 6 hours post-dose on Day 1 of Cycle 2

Population: All randomized participants who received at least 1 dose of capecitabine and had data for AUC 0-tlast analysis.

AUC0-tlast for Capecitabine, 5'-deoxy-5-fluorouridine (5'-DFUR) and 5-fluorouracil (5-FU) was calculated from the plasma concentration-time data for each analyte for Cycle 2, Day 1.

Outcome measures

Outcome measures
Measure	Capecitabine + Enzastaurin n=8 Participants Capecitabine: 1250 milligrams per square meter (mg/m\^2), twice daily (BID) on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Enzastaurin: 1125 1125-milligram (mg) loading dose on Day 1 of Cycle 1, then 500 mg daily on subsequent days to complete 21-day cycles until progressive disease.	Capecitabine + Placebo n=8 Participants Capecitabine: 1250 mg/m\^2, BID on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Placebo: taken as 4 tablets orally, daily, to complete 21-day cycles until progressive disease.
Pharmacokinetics: Area Under the Concentration Curve Versus Time From Time 0 to Last Quantifiable Value (AUC0-tlast) of Capecitabine Capecitabine	6.09 microgramshour/milliliter (ughr/mL) Geometric Coefficient of Variation 57	4.18 microgramshour/milliliter (ughr/mL) Geometric Coefficient of Variation 70
Pharmacokinetics: Area Under the Concentration Curve Versus Time From Time 0 to Last Quantifiable Value (AUC0-tlast) of Capecitabine 5'-deoxy-5-fluorouridine (5'-DFUR)	11.6 microgramshour/milliliter (ughr/mL) Geometric Coefficient of Variation 44	11.0 microgramshour/milliliter (ughr/mL) Geometric Coefficient of Variation 31
Pharmacokinetics: Area Under the Concentration Curve Versus Time From Time 0 to Last Quantifiable Value (AUC0-tlast) of Capecitabine 5-fluorouracil (5-FU)	0.683 microgramshour/milliliter (ughr/mL) Geometric Coefficient of Variation 60	0.358 microgramshour/milliliter (ughr/mL) Geometric Coefficient of Variation 42

SECONDARY outcome

Timeframe: From pre-dose to 6 hours post-dose on Day 1 of Cycle 2

Population: All randomized participants who received at least 1 dose of capecitabine and had data for Cmax analysis.

Cmax for Capecitabine, 5'-deoxy-5-fluorouridine (5'-DFUR) and its metabolites 5-fluorouracil (5-FU) was calculated from the plasma concentration-time data for each analyte for Day 1 of Cycle 2.

Outcome measures

Outcome measures
Measure	Capecitabine + Enzastaurin n=8 Participants Capecitabine: 1250 milligrams per square meter (mg/m\^2), twice daily (BID) on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Enzastaurin: 1125 1125-milligram (mg) loading dose on Day 1 of Cycle 1, then 500 mg daily on subsequent days to complete 21-day cycles until progressive disease.	Capecitabine + Placebo n=8 Participants Capecitabine: 1250 mg/m\^2, BID on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Placebo: taken as 4 tablets orally, daily, to complete 21-day cycles until progressive disease.
Pharmacokinetics: Maximum Observed Concentration (Cmax) of Capecitabine Capecitabine	4.42 micrograms/milliliter(ug/mL) Geometric Coefficient of Variation 88	2.75 micrograms/milliliter(ug/mL) Geometric Coefficient of Variation 114
Pharmacokinetics: Maximum Observed Concentration (Cmax) of Capecitabine 5-DFUR	6.09 micrograms/milliliter(ug/mL) Geometric Coefficient of Variation 80	6.05 micrograms/milliliter(ug/mL) Geometric Coefficient of Variation 69
Pharmacokinetics: Maximum Observed Concentration (Cmax) of Capecitabine 5-FU	0.374 micrograms/milliliter(ug/mL) Geometric Coefficient of Variation 113	0.206 micrograms/milliliter(ug/mL) Geometric Coefficient of Variation 73

SECONDARY outcome

Timeframe: Randomization to last visit (up to 9.66 months)

Population: Intent-to-treat (ITT) population: All randomized participants who received at least 1 dose of study drug.

Response rate was defined as percent of participants with objective response \[CR or PR\] over randomized and treated participants using the Response Evaluation Criteria in Solid Tumors (RECIST v1.0) Guidelines. CR was defined as the disappearance of all tumor lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum of LDs or complete disappearance of target lesions, with persistence (but not worsening) of one or more non-target lesions. No new lesions may have appeared.

Outcome measures

Outcome measures
Measure	Capecitabine + Enzastaurin n=42 Participants Capecitabine: 1250 milligrams per square meter (mg/m\^2), twice daily (BID) on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Enzastaurin: 1125 1125-milligram (mg) loading dose on Day 1 of Cycle 1, then 500 mg daily on subsequent days to complete 21-day cycles until progressive disease.	Capecitabine + Placebo n=43 Participants Capecitabine: 1250 mg/m\^2, BID on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Placebo: taken as 4 tablets orally, daily, to complete 21-day cycles until progressive disease.
Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate)	11.9 percentage of participants Interval 4.0 to 26.0	11.6 percentage of participants Interval 4.0 to 25.0

SECONDARY outcome

Timeframe: Randomization to last visit (up to 9.66 months)

Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study drug with a CR or PR. Participants censored: Capecitabine + Enzastaurin = 3; Capecitabine + Placebo = 2.

The DOR was defined as the time from first objective status assessment of complete response (CR) or partial response (PR) to the first time of progression or death as a result of any cause. According to the Response Evaluation Criteria in Solid Tumors (RECIST V1.0) criteria, CR was the disappearance of all tumor lesions. PR was at least a 30% decrease in the sum of the longest diameter (LD) of target lesions or complete disappearance of target lesions, with persistence (but not worsening) of 1 or more non-target lesions, with occurrence of no new lesions. For participants not known to have died as of the data cut-off date and who did not have progressive disease, DOR was censored at the date of last visit with adequate assessment. For participants who received subsequent anticancer therapy (after discontinuation from the study treatment) prior to disease progression or death, DOR was censored at the date of last visit with adequate assessment.

Outcome measures

Outcome measures
Measure	Capecitabine + Enzastaurin n=5 Participants Capecitabine: 1250 milligrams per square meter (mg/m\^2), twice daily (BID) on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Enzastaurin: 1125 1125-milligram (mg) loading dose on Day 1 of Cycle 1, then 500 mg daily on subsequent days to complete 21-day cycles until progressive disease.	Capecitabine + Placebo n=5 Participants Capecitabine: 1250 mg/m\^2, BID on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Placebo: taken as 4 tablets orally, daily, to complete 21-day cycles until progressive disease.
Duration of Response (DOR)	4.27 months Interval 2.17 to 4.27	3.47 months Interval 2.79 to Not evaluable due to too few data points.

SECONDARY outcome

Timeframe: Randomization to date of death from any cause up to 20.83 months

Population: Intent-to-treat (ITT) population: All randomized participants who received at least 1 dose of study drug. Participants censored: Capecitabine + Enzastaurin = 23; Capecitabine + Placebo = 28.

OS was defined as the time in months from the date of study enrollment to the date of death from any cause. For participants not known to have died as of the cut-off date, OS was censored at the last contact date.

Outcome measures

Outcome measures
Measure	Capecitabine + Enzastaurin n=42 Participants Capecitabine: 1250 milligrams per square meter (mg/m\^2), twice daily (BID) on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Enzastaurin: 1125 1125-milligram (mg) loading dose on Day 1 of Cycle 1, then 500 mg daily on subsequent days to complete 21-day cycles until progressive disease.	Capecitabine + Placebo n=43 Participants Capecitabine: 1250 mg/m\^2, BID on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Placebo: taken as 4 tablets orally, daily, to complete 21-day cycles until progressive disease.
Overall Survival (OS)	9.86 months Interval 7.03 to 16.59	14.88 months Interval 9.86 to 19.32

SECONDARY outcome

Timeframe: Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up]

Data presented are the number of participants who experienced serious AEs, AEs, death due to progressive disease (PD), death due to AEs while on treatment and death during the 30-day post-treatment. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.

Outcome measures

Outcome measures
Measure	Capecitabine + Enzastaurin n=42 Participants Capecitabine: 1250 milligrams per square meter (mg/m\^2), twice daily (BID) on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Enzastaurin: 1125 1125-milligram (mg) loading dose on Day 1 of Cycle 1, then 500 mg daily on subsequent days to complete 21-day cycles until progressive disease.	Capecitabine + Placebo n=43 Participants Capecitabine: 1250 mg/m\^2, BID on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Placebo: taken as 4 tablets orally, daily, to complete 21-day cycles until progressive disease.
Pharmacology Toxicity and Adverse Events (AEs) Deaths in 30-day follow-up	6 Participants	1 Participants
Pharmacology Toxicity and Adverse Events (AEs) Serious AEs	12 Participants	12 Participants
Pharmacology Toxicity and Adverse Events (AEs) Other non-serious AEs	38 Participants	40 Participants
Pharmacology Toxicity and Adverse Events (AEs) Deaths Due to PD	13 Participants	12 Participants
Pharmacology Toxicity and Adverse Events (AEs) Deaths Due to AEs	4 Participants	2 Participants

Adverse Events

A - Capecitabine + Enzastaurin

Serious events: 12 serious events

Other events: 38 other events

Deaths: 0 deaths

B - Capecitabine + Placebo

Serious events: 12 serious events

Other events: 40 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	A - Capecitabine + Enzastaurin n=42 participants at risk Capecitabine: 1250 milligrams per square meter (mg/m\^2) twice daily (BID) on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Enzastaurin: 1125-milligram (mg) loading dose on Day 1 of Cycle 1, then 500 mg daily on subsequent days to complete 21-day cycles until progressive disease.	B - Capecitabine + Placebo n=43 participants at risk Capecitabine: 1250 mg/m\^2 BID on Days 1-14 followed by a 1-week rest period (Days 15-21) for each 21-day cycle until progressive disease. Placebo: 4 tablets orally, daily, to complete 21-day cycles until progressive disease.
Blood and lymphatic system disorders Febrile neutropenia	7.1% 3/42 • Number of events 3 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	0.00% 0/43 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Blood and lymphatic system disorders Leukopenia	2.4% 1/42 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	2.3% 1/43 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/42 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	2.3% 1/43 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Cardiac disorders Atrial fibrillation	0.00% 0/42 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	2.3% 1/43 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Cardiac disorders Cardio-respiratory arrest	2.4% 1/42 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	2.3% 1/43 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Cardiac disorders Pericardial effusion	0.00% 0/42 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	4.7% 2/43 • Number of events 2 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Gastrointestinal disorders Diarrhoea	7.1% 3/42 • Number of events 3 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	2.3% 1/43 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Gastrointestinal disorders Vomiting	4.8% 2/42 • Number of events 2 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	0.00% 0/43 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
General disorders Mucosal inflammation	0.00% 0/42 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	2.3% 1/43 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
General disorders Sudden death	2.4% 1/42 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	0.00% 0/43 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Hepatobiliary disorders Portal vein thrombosis	0.00% 0/42 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	2.3% 1/43 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Infections and infestations Pneumonia	2.4% 1/42 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	0.00% 0/43 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Infections and infestations Sepsis	2.4% 1/42 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	0.00% 0/43 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Infections and infestations Septic shock	0.00% 0/42 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	2.3% 1/43 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Injury, poisoning and procedural complications Acetabulum fracture	0.00% 0/42 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	2.3% 1/43 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Investigations Biopsy	0.00% 0/42 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	2.3% 1/43 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Metabolism and nutrition disorders Dehydration	4.8% 2/42 • Number of events 2 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	2.3% 1/43 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Metabolism and nutrition disorders Hypercalcaemia	0.00% 0/42 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	2.3% 1/43 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	2.4% 1/42 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	0.00% 0/43 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Nervous system disorders Coma	2.4% 1/42 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	0.00% 0/43 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Nervous system disorders Convulsion	0.00% 0/42 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	2.3% 1/43 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Respiratory, thoracic and mediastinal disorders Pleural effusion	4.8% 2/42 • Number of events 2 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	4.7% 2/43 • Number of events 2 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	2.4% 1/42 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	7.0% 3/43 • Number of events 3 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Respiratory, thoracic and mediastinal disorders Respiratory acidosis	2.4% 1/42 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	0.00% 0/43 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Respiratory, thoracic and mediastinal disorders Respiratory failure	2.4% 1/42 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.	2.3% 1/43 • Number of events 1 • Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] Study-specific clinical outcomes due to progressive disease (PD) were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.