Trial Outcomes & Findings for A Study to Assess Capecitabine (Xeloda®) in Patients With Locally Advanced or Metastatic Breast Cancer (NCT NCT00077857)

Last Updated: 2013-05-10

Results Overview

Progression Free Survival was defined as the time from the date of randomization to the day of documented disease progression or death due to any cause.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

470 participants

Primary outcome timeframe

Event driven (after 350 events). Median observation time was approximately 16 months.

Results posted on

2013-05-10

Participant Flow

Participant milestones

Participant milestones
Measure	1250 mg/m^2 Capecitabine + Docetaxel 1250 mg/m\^2 capecitabine (Xeloda®) orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel (Taxotere®) 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.	825 mg/m^2 Capecitabine + Docetaxel 825 mg/m\^2 capecitabine orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.
Overall Study STARTED	235	235
Overall Study Received Study Drug	231	234
Overall Study Safety Population: Actual Dose Received	217	248
Overall Study COMPLETED	34	31
Overall Study NOT COMPLETED	201	204

Reasons for withdrawal

Reasons for withdrawal
Measure	1250 mg/m^2 Capecitabine + Docetaxel 1250 mg/m\^2 capecitabine (Xeloda®) orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel (Taxotere®) 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.	825 mg/m^2 Capecitabine + Docetaxel 825 mg/m\^2 capecitabine orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.
Overall Study Adverse Event	30	32
Overall Study Death	7	3
Overall Study Insufficient therapeutic response	112	128
Overall Study Violation of selection criteria at entry	3	1
Overall Study Other protocol violation	0	1
Overall Study Refused treatment	29	21
Overall Study Failure to return	5	5
Overall Study Other	15	13

Baseline Characteristics

A Study to Assess Capecitabine (Xeloda®) in Patients With Locally Advanced or Metastatic Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	1250 mg/m^2 Capecitabine + Docetaxel n=235 Participants 1250 mg/m\^2 capecitabine (Xeloda®) orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel (Taxotere®) 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.	825 mg/m^2 Capecitabine + Docetaxel n=235 Participants 825 mg/m\^2 capecitabine orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.	Total n=470 Participants Total of all reporting groups
Age Continuous	50.9 years n=5 Participants	50.6 years n=7 Participants	50.75 years n=5 Participants
Sex: Female, Male Female	235 Participants n=5 Participants	235 Participants n=7 Participants	470 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Event driven (after 350 events). Median observation time was approximately 16 months.

Population: Per protocol population included all participants who received at least one dose of study and who did not have any major protocol deviations.

Progression Free Survival was defined as the time from the date of randomization to the day of documented disease progression or death due to any cause.

Outcome measures

Outcome measures
Measure	1250 mg/m^2 Capecitabine + Docetaxel n=230 Participants 1250 mg/m\^2 capecitabine (Xeloda®) orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel (Taxotere®) 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.	825 mg/m^2 Capecitabine + Docetaxel n=229 Participants 825 mg/m\^2 capecitabine orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.
Time to Progression of Disease or Death	7.9 Months Interval 6.9 to 8.5	5.8 Months Interval 4.9 to 7.1

SECONDARY outcome

Timeframe: Until Progressive Disease (PD) or end of primary study treatment (up to 16 cycles) plus 28 days.

Population: Intent to treat population included all randomized participants.

According to Response Evaluation Criteria in Solid Tumors (RECIST) criteria: CR is defined as the disappearance of all target lesions and PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the nadir sum LD.

Outcome measures

Outcome measures
Measure	1250 mg/m^2 Capecitabine + Docetaxel n=235 Participants 1250 mg/m\^2 capecitabine (Xeloda®) orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel (Taxotere®) 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.	825 mg/m^2 Capecitabine + Docetaxel n=235 Participants 825 mg/m\^2 capecitabine orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.
Percentage of Participants With Best Overall Response Being Complete Response (CR) or Partial Response (PR)	45.1 Percentage of participants Interval 38.6 to 51.7	37.4 Percentage of participants Interval 31.2 to 44.0

SECONDARY outcome

Timeframe: Until PD or end of primary study treatment (up to 16 cycles) plus 28 days.

Population: Intent to treat population included all randomized participants.

For patients with Best Overall Response being Complete Response (CR) or Partial Response (PR), time to response was measured as the time from randomization to the first time when the measurement criteria for CR or PR were met. The percentage of participants with overall response within the given time ranges in each of the categories: Weeks 1-6, 7-12, 13-18, 19-24, 25-30, 31-36, and 43-48 are reported.

Outcome measures

Outcome measures
Measure	1250 mg/m^2 Capecitabine + Docetaxel n=235 Participants 1250 mg/m\^2 capecitabine (Xeloda®) orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel (Taxotere®) 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.	825 mg/m^2 Capecitabine + Docetaxel n=235 Participants 825 mg/m\^2 capecitabine orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.
Time to Overall Response Week 1-6	25 Percentage of participants	30 Percentage of participants
Time to Overall Response Week 7-12	48 Percentage of participants	30 Percentage of participants
Time to Overall Response Week 13-18	20 Percentage of participants	17 Percentage of participants
Time to Overall Response Week 19-24	7 Percentage of participants	7 Percentage of participants
Time to Overall Response Week 25-30	3 Percentage of participants	1 Percentage of participants
Time to Overall Response Week 31-36	3 Percentage of participants	2 Percentage of participants
Time to Overall Response Week 43-48	0 Percentage of participants	1 Percentage of participants

SECONDARY outcome

Timeframe: Until PD or death. Median duration of response was approximately 7 months.

Population: Intent to treat population included all randomized participants.

Duration of overall response was measured from the time that measurement criteria were first met for Complete Response or Partial Response until the first date that progressive disease or death was documented.

Outcome measures

Outcome measures
Measure	1250 mg/m^2 Capecitabine + Docetaxel n=235 Participants 1250 mg/m\^2 capecitabine (Xeloda®) orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel (Taxotere®) 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.	825 mg/m^2 Capecitabine + Docetaxel n=235 Participants 825 mg/m\^2 capecitabine orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.
Duration of Overall Response	6.9 Months Interval 6.1 to 8.6	6.9 Months Interval 5.8 to 9.0

SECONDARY outcome

Timeframe: Until premature withdrawal or end of primary study treatment (up to 16 cycles).

Population: Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to 1250 mg/m\^2 actual received an initial dose that ranged from 480 to 984 mg/m\^2 so are included in the 825 mg/m\^2 arm for safety.

The time to treatment failure was the time from the date of randomization to the first occurrence of any of the following events: * adverse events * insufficient therapeutic response (disease progression) * death * failure to return * refusing treatment/being unwilling to cooperate * withdrawing consent.

Outcome measures

Outcome measures
Measure	1250 mg/m^2 Capecitabine + Docetaxel n=217 Participants 1250 mg/m\^2 capecitabine (Xeloda®) orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel (Taxotere®) 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.	825 mg/m^2 Capecitabine + Docetaxel n=248 Participants 825 mg/m\^2 capecitabine orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.
Time to Treatment Failure	5.1 Months Interval 4.2 to 5.8	4.6 Months Interval 4.1 to 5.3

SECONDARY outcome

Timeframe: Throughout the study. Median observation time was approximately 16 months.

Population: Intent to treat population included all randomized participants.

Overall Survival was measured as the time from the date of randomization to the date of death.

Outcome measures

Outcome measures
Measure	1250 mg/m^2 Capecitabine + Docetaxel n=235 Participants 1250 mg/m\^2 capecitabine (Xeloda®) orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel (Taxotere®) 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.	825 mg/m^2 Capecitabine + Docetaxel n=235 Participants 825 mg/m\^2 capecitabine orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.
Overall Survival	16.4 Months Interval 13.6 to 21.8	15.1 Months Interval 12.9 to 17.7

SECONDARY outcome

Timeframe: First study drug intake until last study drug intake plus 28 days

An adverse event was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events. A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is Life-Threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. Additional information about Adverse Events can be found in the Adverse Event Section.

Outcome measures

Outcome measures
Measure	1250 mg/m^2 Capecitabine + Docetaxel n=217 Participants 1250 mg/m\^2 capecitabine (Xeloda®) orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel (Taxotere®) 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.	825 mg/m^2 Capecitabine + Docetaxel n=248 Participants 825 mg/m\^2 capecitabine orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.
Number of Participants With Adverse Events and Serious Adverse Events Adverse Events	206 Participants	234 Participants
Number of Participants With Adverse Events and Serious Adverse Events Serious Adverse Events	41 Participants	53 Participants

Adverse Events

1250 mg/m^2 Capecitabine + Docetaxel

Serious events: 41 serious events

Other events: 192 other events

Deaths: 0 deaths

825 mg/m^2 Capecitabine + Docetaxel

Serious events: 53 serious events

Other events: 223 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffman-LaRoche

Phone: 800-821-8590

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	1250 mg/m^2 Capecitabine + Docetaxel n=217 participants at risk 1250 mg/m\^2 capecitabine (Xeloda®) orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel (Taxotere®) 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.	825 mg/m^2 Capecitabine + Docetaxel n=248 participants at risk 825 mg/m\^2 capecitabine orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.
Gastrointestinal disorders Stomatitis all	40.1% 87/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	35.5% 88/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Gastrointestinal disorders Diarrhoea	33.6% 73/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	32.7% 81/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Gastrointestinal disorders Nausea	20.7% 45/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	23.4% 58/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Gastrointestinal disorders Vomiting	15.2% 33/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	18.1% 45/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Gastrointestinal disorders Constipation	7.8% 17/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	6.9% 17/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Gastrointestinal disorders Abdominal pain	6.5% 14/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	3.6% 9/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Skin and subcutaneous tissue disorders Palmar-Plantar erythrodysaesthesia syndrome	47.0% 102/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	41.9% 104/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Skin and subcutaneous tissue disorders Alopecia	34.1% 74/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	33.1% 82/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Skin and subcutaneous tissue disorders Nail disorder	12.0% 26/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	15.3% 38/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Skin and subcutaneous tissue disorders Rash	6.5% 14/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	5.2% 13/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
General disorders Fatigue	26.7% 58/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	20.2% 50/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
General disorders Pyrexia	16.1% 35/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	10.9% 27/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
General disorders Asthenia	12.0% 26/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	13.7% 34/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
General disorders Oedema peripheral	8.3% 18/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	10.5% 26/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Blood and lymphatic system disorders Neutropenia	35.5% 77/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	28.2% 70/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Blood and lymphatic system disorders Leukopenia	9.7% 21/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	6.9% 17/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Blood and lymphatic system disorders Anaemia	6.0% 13/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	6.0% 15/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Respiratory, thoracic and mediastinal disorders Cough	7.4% 16/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	8.9% 22/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Respiratory, thoracic and mediastinal disorders Dyspnoea	5.5% 12/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	7.7% 19/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	3.7% 8/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	5.6% 14/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Metabolism and nutrition disorders Decreased appetite	13.8% 30/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	14.5% 36/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Investigations Blood bilirubin increased	8.3% 18/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	6.0% 15/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Investigations Aspartate aminotransferase increased	5.1% 11/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	2.8% 7/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Musculoskeletal and connective tissue disorders Myalgia	6.9% 15/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	12.5% 31/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Nervous system disorders Headache	6.5% 14/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	4.8% 12/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.
Hepatobiliary disorders Hyperbilirubinaemia	6.0% 13/217 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.	4.0% 10/248 Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.