Trial Outcomes & Findings for Phase III Trial Comparing Capecitabine in Combination With Sorafenib or Placebo in the Treatment of Locally Advanced or Metastatic HER2-Negative Breast Cancer (NCT NCT01234337)

Last Updated: 2018-11-06

Results Overview

PFS was defined as the time from date of randomization to disease progression, radiological or death due to any cause, whichever occurs first. Per RECIST version 1.1, progressive disease was determined when there was at least 20% increase in the sum of diameters of the target lesions, taking as a reference the smallest sum on study (this included the baseline sum if that was the smallest sum on trial). In addition to a relative increase of 20%, the sum had demonstrated an absolute increase of at least 5 mm. Appearance of new lesions and unequivocal progression of existing non-target lesions was also interpreted as progressive disease. Participants without progression or death at the time of analysis were censored at their last date of evaluable tumor evaluation. Median and other 95% confidence intervals (CIs) computed using Kaplan-Meier estimates.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

537 participants

Primary outcome timeframe

From randomization of the first participant until approximately 3 years or until disease radiological progression

Results posted on

2018-11-06

Participant Flow

At 154 sites in 22 countries, participants with histologically or cytologically confirmed human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the breast, and locally advanced or metastatic disease, were screened.

Of 707 participants screened, 537 participants were randomized and 527 participants received at least 1 dose of study treatment. The reasons for 170 screen failures were adverse event in 21 participants, disease progression, recurrence or relapse in 2, consent withdrawn in 16, death in 4, and protocol violation in 127 participants.

Participant milestones

Participant milestones
Measure	Sorafenib (Nexavar, BAY43-9006) + Capecitabine Sorafenib tablets were administered orally continuously at a total daily dose of 600 mg (200 mg in the morning, 400 mg in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and sorafenib dose to a total daily dose of 800 mg for that participant.	Placebo + Capecitabine Placebo tablets matching with sorafenib were administered orally continuously (1 tablet in the morning, 2 tablets in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that participant.
Overall Study STARTED	266	271
Overall Study Participants Received Treatment	260	267
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	266	271

Reasons for withdrawal

Reasons for withdrawal
Measure	Sorafenib (Nexavar, BAY43-9006) + Capecitabine Sorafenib tablets were administered orally continuously at a total daily dose of 600 mg (200 mg in the morning, 400 mg in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and sorafenib dose to a total daily dose of 800 mg for that participant.	Placebo + Capecitabine Placebo tablets matching with sorafenib were administered orally continuously (1 tablet in the morning, 2 tablets in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that participant.
Overall Study Adverse Event	58	21
Overall Study Disease progression/recurrence/relapse	181	223
Overall Study Investi. decision not protocol driven	5	6
Overall Study Non-compliant with study medication	3	2
Overall Study Randomized but not treated	6	4
Overall Study Lost to Follow-up	0	1
Overall Study Protocol Violation	2	3
Overall Study Withdrawal by Subject	11	9
Overall Study Death	0	1
Overall Study Switch to commercial drug	0	1

Baseline Characteristics

Phase III Trial Comparing Capecitabine in Combination With Sorafenib or Placebo in the Treatment of Locally Advanced or Metastatic HER2-Negative Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sorafenib (Nexavar, BAY43-9006) + Capecitabine n=266 Participants Sorafenib tablets were administered orally continuously at a total daily dose of 600 mg (200 mg in the morning, 400 mg in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and sorafenib dose to a total daily dose of 800 mg for that participant.	Placebo + Capecitabine n=271 Participants Placebo tablets matching with sorafenib were administered orally continuously (1 tablet in the morning, 2 tablets in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that participant.	Total n=537 Participants Total of all reporting groups
Age, Continuous	53.3 years STANDARD_DEVIATION 10.2 • n=5 Participants	54.4 years STANDARD_DEVIATION 10.9 • n=7 Participants	53.9 years STANDARD_DEVIATION 10.6 • n=5 Participants
Sex: Female, Male Female	265 Participants n=5 Participants	268 Participants n=7 Participants	533 Participants n=5 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized White	205 Participants n=5 Participants	212 Participants n=7 Participants	417 Participants n=5 Participants
Race/Ethnicity, Customized Black	7 Participants n=5 Participants	4 Participants n=7 Participants	11 Participants n=5 Participants
Race/Ethnicity, Customized Asian	50 Participants n=5 Participants	50 Participants n=7 Participants	100 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic	4 Participants n=5 Participants	5 Participants n=7 Participants	9 Participants n=5 Participants
Region of Enrollment Europe	166 Participants n=5 Participants	168 Participants n=7 Participants	334 Participants n=5 Participants
Region of Enrollment North America	23 Participants n=5 Participants	26 Participants n=7 Participants	49 Participants n=5 Participants
Region of Enrollment Other	77 Participants n=5 Participants	77 Participants n=7 Participants	154 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) ECOG status=0	152 Participants n=5 Participants	161 Participants n=7 Participants	313 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) ECOG status=1	114 Participants n=5 Participants	110 Participants n=7 Participants	224 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) ECOG status=2	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) ECOG status=3	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) ECOG status=4	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Number of Prior Chemotherapies for Metastatic Disease Prior chemotherapies=0	114 Participants n=5 Participants	118 Participants n=7 Participants	232 Participants n=5 Participants
Number of Prior Chemotherapies for Metastatic Disease Prior chemotherapies=1	152 Participants n=5 Participants	153 Participants n=7 Participants	305 Participants n=5 Participants
Hormone Receptor Status Negative	83 Participants n=5 Participants	84 Participants n=7 Participants	167 Participants n=5 Participants
Hormone Receptor Status Positive	183 Participants n=5 Participants	187 Participants n=7 Participants	370 Participants n=5 Participants
Visceral Disease at Baseline Missing	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Visceral Disease at Baseline No	66 Participants n=5 Participants	57 Participants n=7 Participants	123 Participants n=5 Participants
Visceral Disease at Baseline Yes	199 Participants n=5 Participants	213 Participants n=7 Participants	412 Participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization of the first participant until approximately 3 years or until disease radiological progression

Population: Full Analysis Set (FAS), also considered as Intent-to-treat (ITT) set, was defined as all randomized participants even if randomized but received no drug or if randomized and initially received incorrect drug prior to switching to correct study drug, these were included in FAS.

Outcome measures

Outcome measures
Measure	Sorafenib (Nexavar, BAY43-9006) + Capecitabine n=266 Participants Sorafenib tablets were administered orally continuously at a total daily dose of 600 mg (200 mg in the morning, 400 mg in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and sorafenib dose to a total daily dose of 800 mg for that participant.	Placebo + Capecitabine n=271 Participants Placebo tablets matching with sorafenib were administered orally continuously (1 tablet in the morning, 2 tablets in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that participant.
Progression-free Survival (PFS) Assessed by the Independent Review Panel According to Response Evaluation Criteria for Solid Tumors (RECIST) 1.1	166 days Interval 131.0 to 206.0	165 days Interval 126.0 to 204.0

SECONDARY outcome

Timeframe: From randomization of the first participant until approximately 3 years later

Population: FAS

OS was defined as the time from date of randomization to death due to any cause. Participants still alive at the time of analysis were censored at their last known alive date. Median and other 95% CIs computed using Kaplan-Meier estimates.

Outcome measures

Outcome measures
Measure	Sorafenib (Nexavar, BAY43-9006) + Capecitabine n=266 Participants Sorafenib tablets were administered orally continuously at a total daily dose of 600 mg (200 mg in the morning, 400 mg in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and sorafenib dose to a total daily dose of 800 mg for that participant.	Placebo + Capecitabine n=271 Participants Placebo tablets matching with sorafenib were administered orally continuously (1 tablet in the morning, 2 tablets in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that participant.
Overall Survival (OS)	575 days Interval 467.0 to 645.0	616 days Interval 546.0 to 687.0

SECONDARY outcome

Timeframe: From randomization of the first participant until approximately 3 years later or until disease radiological progression

Population: FAS

TTP was defined as the time from date of randomization to disease radiological progression by central review. Per RECIST version 1.1, progressive disease was determined when there was at least 20% increase in the sum of diameters of the target lesions, taking as a reference the smallest sum on study (this included the baseline sum if that was the smallest sum on trial). In addition to a relative increase of 20%, the sum had demonstrated an absolute increase of at least 5 mm. Appearance of new lesions and unequivocal progression of existing non-target lesions was also interpreted as progressive disease. Participants without progression or death at the time of analysis were censored at their last date of evaluable tumor evaluation. Median and other 95% confidence intervals (CIs) computed using Kaplan-Meier estimates.

Outcome measures

Outcome measures
Measure	Sorafenib (Nexavar, BAY43-9006) + Capecitabine n=266 Participants Sorafenib tablets were administered orally continuously at a total daily dose of 600 mg (200 mg in the morning, 400 mg in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and sorafenib dose to a total daily dose of 800 mg for that participant.	Placebo + Capecitabine n=271 Participants Placebo tablets matching with sorafenib were administered orally continuously (1 tablet in the morning, 2 tablets in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that participant.
Time to Progression (TTP) by Central Review	168 days Interval 139.0 to 215.0	165 days Interval 127.0 to 208.0

SECONDARY outcome

Timeframe: From randomization of the first participant until approximately 3 years later or until disease radiological progression

Population: FAS

ORR was defined as the best tumor response (Complete Response \[CR\] or Partial Response \[PR\]) observed during treatment or within 30 days after termination of study treatment, assessed according to the RECIST version 1.1. CR=all target lesions disappeared, and any pathological lymph node, whether target or non-target, had a reduction in short axis to \<10 mm. If any residual lesion was present, cyto-histology was made available to unequivocally document benignity. PR=at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR=CR+PR. CR and PR were confirmed by another scan at least 4 weeks later.

Outcome measures

Outcome measures
Measure	Sorafenib (Nexavar, BAY43-9006) + Capecitabine n=266 Participants Sorafenib tablets were administered orally continuously at a total daily dose of 600 mg (200 mg in the morning, 400 mg in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and sorafenib dose to a total daily dose of 800 mg for that participant.	Placebo + Capecitabine n=271 Participants Placebo tablets matching with sorafenib were administered orally continuously (1 tablet in the morning, 2 tablets in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that participant.
Objective Response Rate (ORR) by Central Review	13.5 Percentage (%) of participants Interval 9.7 to 18.2	15.5 Percentage (%) of participants Interval 11.4 to 20.4

SECONDARY outcome

Timeframe: From randomization of the first participant until approximately 3 years later or until disease radiological progression

Population: FAS

DCR was defined as the proportion of participants whose best response was CR, PR, stable disease (SD) or Non-CR/Non-PD. Per RECIST version 1.1, CR=all target lesions disappeared, any pathological lymph node, target/non-target, a reduction in short axis to \<10 mm. PR=at least 30% decrease in the sum of diameters of target lesions taking as reference baseline sum diameters. PD=at least 20% increase in the sum of diameters of the target lesions, taking as a reference smallest sum on study. Appearance of new lesions and unequivocal progression of existing non-target lesions. SD=neither sufficient shrinkage qualified for PR nor sufficient increase qualified for PD, taking smallest sum of diameters as a reference. Non-CR/Non-PD=persistence of 1/more non-target lesion(s) and/or maintenance of tumor marker level above normal limits. DCR=CR+PR+SD or Non-CR/Non-PD. CR and PR confirmed by another scan at least 4 weeks later. SD and Non-CR/Non-PD documented at least 6 weeks after randomization.

Outcome measures

Outcome measures
Measure	Sorafenib (Nexavar, BAY43-9006) + Capecitabine n=266 Participants Sorafenib tablets were administered orally continuously at a total daily dose of 600 mg (200 mg in the morning, 400 mg in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and sorafenib dose to a total daily dose of 800 mg for that participant.	Placebo + Capecitabine n=271 Participants Placebo tablets matching with sorafenib were administered orally continuously (1 tablet in the morning, 2 tablets in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that participant.
Disease Control Rate (DCR) by Central Review	60.5 percentage (%) of participants Interval 54.4 to 66.4	58.3 percentage (%) of participants Interval 52.2 to 64.2

SECONDARY outcome

Timeframe: From randomization of the first participant until approximately 3 years later or until disease radiological progression

Population: Only responders in FAS were evaluated for this outcome measure.

DOR was defined as the time from date of first response (CR or PR) to the date when PD is first documented, or to the date of death, whichever occurred first according to RECIST version 1.1. CR=all target lesions disappeared, and any pathological lymph node, whether target or non-target, had a reduction in short axis to \<10 mm. If any residual lesion was present, cyto-histology was made available to unequivocally document benignity. PR=at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants still having CR or PR and have not died at the time of analysis were censored at their last date of tumor evaluation. DOR defined for confirmed responders only (that is, CR or PR). 'NA' indicates that value could not be estimated due to censored data. Median and 95% CIs were computed using Kaplan-Meier estimates.

Outcome measures

Outcome measures
Measure	Sorafenib (Nexavar, BAY43-9006) + Capecitabine n=36 Participants Sorafenib tablets were administered orally continuously at a total daily dose of 600 mg (200 mg in the morning, 400 mg in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and sorafenib dose to a total daily dose of 800 mg for that participant.	Placebo + Capecitabine n=42 Participants Placebo tablets matching with sorafenib were administered orally continuously (1 tablet in the morning, 2 tablets in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that participant.
Duration of Response (DOR) by Central Reader	313 days Interval 209.0 to Value could not be estimated due to censored data.	290 days Interval 169.0 to Value could not be estimated due to censored data.

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 1 of Cycles 1, 3, 5, 7, 9, 11, 13, 16, 19, 22, 25, 28, 31, 34, 37, and end of treatment (EOT, 21 days after last dose of study drug)

Population: FAS participants with a baseline assessment and at least one post-baseline assessment during the study.

The FBSI-8 was an 8-item questionnaire. Participants responded to each item using a 5-point Likert-type scale ranging from 0 (not at all) to 4 (very much). A total scale score was calculated (range from 0 to 32), with higher scores indicating low symptomatology and reflecting a better Health-Related Quality of Life (HRQoL). The results on the analysis of covariance (ANCOVA) of time-adjusted area under curve (AUC) for the FBSI-8 score were reported. The time-adjusted AUC was calculated by dividing the AUC by duration (in days) over the period of interest, and reported as 'scores on a scale'.

Outcome measures

Outcome measures
Measure	Sorafenib (Nexavar, BAY43-9006) + Capecitabine n=233 Participants Sorafenib tablets were administered orally continuously at a total daily dose of 600 mg (200 mg in the morning, 400 mg in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and sorafenib dose to a total daily dose of 800 mg for that participant.	Placebo + Capecitabine n=243 Participants Placebo tablets matching with sorafenib were administered orally continuously (1 tablet in the morning, 2 tablets in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that participant.
Patient Reported Outcomes: Functional Assessment of Cancer Therapy-Breast Symptom Index (8 Item) (FBSI-8)	20.915 Scores on a scale Interval 20.459 to 21.37	21.356 Scores on a scale Interval 20.911 to 21.801

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 1 of Cycles 1, 3, 5, 7, 9, 11, 13, 16, 19, 22, 25, 28, and EOT (21 days after last dose of study drug)

Population: FAS participants with a baseline assessment and at least one post-baseline assessment during the study.

The EQ-5D was a generic Quality of life (QoL) based instrument validated in cancer populations. EQ-5D questionnaire contained a 5-item descriptive system of health states (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and visual analogue scale (VAS). A single HRQoL score ranging from -0.59 to 1 was generated from standard scoring algorithm developed by the EuroQoL was the EQ-5D index score, higher scores represent better health status. A change of at least 0.10 to 0.12 points was considered clinically meaningful. The results on the ANCOVA of time-adjusted AUC for the EQ-5D - Index Score were reported. The time-adjusted AUC was calculated by dividing the AUC by duration (in days) over the period of interest, and reported as 'scores on a scale'.

Outcome measures

Outcome measures
Measure	Sorafenib (Nexavar, BAY43-9006) + Capecitabine n=236 Participants Sorafenib tablets were administered orally continuously at a total daily dose of 600 mg (200 mg in the morning, 400 mg in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and sorafenib dose to a total daily dose of 800 mg for that participant.	Placebo + Capecitabine n=247 Participants Placebo tablets matching with sorafenib were administered orally continuously (1 tablet in the morning, 2 tablets in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that participant.
Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Index Score	0.665 Scores on a scale Interval 0.641 to 0.688	0.69 Scores on a scale Interval 0.667 to 0.713

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 1 of Cycles 1, 3, 5, 7, 9, 11, 13, 16, 19, 22, 25, 28, and EOT (21 days after last dose of study drug)

Population: FAS participants with a baseline assessment and at least one post-baseline assessment during the study.

The EQ-5D was a generic QoL preference based instrument and has been validated in the cancer populations. VAS was generated from 0 (worst imaginable health state) to 100 (best imaginable health state). This VAS score was referred to as the EQ-5D self-reported health status score. The results on ANCOVA of time-adjusted AUC were reported. The time-adjusted AUC was calculated by dividing the AUC by duration (in days) over the period of interest, and reported as 'scores on a scale'.

Outcome measures

Outcome measures
Measure	Sorafenib (Nexavar, BAY43-9006) + Capecitabine n=235 Participants Sorafenib tablets were administered orally continuously at a total daily dose of 600 mg (200 mg in the morning, 400 mg in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and sorafenib dose to a total daily dose of 800 mg for that participant.	Placebo + Capecitabine n=244 Participants Placebo tablets matching with sorafenib were administered orally continuously (1 tablet in the morning, 2 tablets in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that participant.
Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Visual Analogue Scale (VAS) Score	67.532 Scores on a scale Interval 65.87 to 69.19	69.228 Scores on a scale Interval 67.6 to 70.86

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-dose and 0.5, 1, 2, and 4 hours after capecitabine dosing at Cycle 2, Day 14

Population: Pharmacokinetic Analysis Set (PKS) included all participants with a valid pharmacokinetic profile of capecitabine.

Maximum observed drug concentration, directly taken from analytical data. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. In the listed categories below, 'N' signifies the number of evaluable participants for the drug administered.

Outcome measures

Outcome measures
Measure	Sorafenib (Nexavar, BAY43-9006) + Capecitabine n=56 Participants Sorafenib tablets were administered orally continuously at a total daily dose of 600 mg (200 mg in the morning, 400 mg in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and sorafenib dose to a total daily dose of 800 mg for that participant.	Placebo + Capecitabine n=84 Participants Placebo tablets matching with sorafenib were administered orally continuously (1 tablet in the morning, 2 tablets in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that participant.
Maximum Observed Drug Concentration (Cmax) of Capecitabine and 5-fluorouracil Capecitabine	6.05 milligram per liter Geometric Coefficient of Variation 79	4.68 milligram per liter Geometric Coefficient of Variation 72
Maximum Observed Drug Concentration (Cmax) of Capecitabine and 5-fluorouracil 5-fluorouracil	0.434 milligram per liter Geometric Coefficient of Variation 105	0.382 milligram per liter Geometric Coefficient of Variation 67

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-dose and 0.5, 1, 2, and 4 hours after capecitabine dosing at Cycle 2, Day 14

Population: PKS

AUC(0-tlast) is defined as AUC from time 0 to the last data point, calculated up by linear trapezoidal rule, down by logarithmic trapezoidal rule. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. In the listed categories below, 'N' signifies the number of evaluable participants for the drug administered.

Outcome measures

Outcome measures
Measure	Sorafenib (Nexavar, BAY43-9006) + Capecitabine n=56 Participants Sorafenib tablets were administered orally continuously at a total daily dose of 600 mg (200 mg in the morning, 400 mg in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and sorafenib dose to a total daily dose of 800 mg for that participant.	Placebo + Capecitabine n=84 Participants Placebo tablets matching with sorafenib were administered orally continuously (1 tablet in the morning, 2 tablets in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that participant.
Area Under Curve From Time Zero to Last Quantifiable Concentration (AUC[0-tlast]) of Capecitabine and 5-fluorouracil Capecitabine	7.12 milligram*hour per liter Geometric Coefficient of Variation 50	5.13 milligram*hour per liter Geometric Coefficient of Variation 48
Area Under Curve From Time Zero to Last Quantifiable Concentration (AUC[0-tlast]) of Capecitabine and 5-fluorouracil 5-fluorouracil	0.621 milligram*hour per liter Geometric Coefficient of Variation 71	0.557 milligram*hour per liter Geometric Coefficient of Variation 47

OTHER_PRE_SPECIFIED outcome

Timeframe: From the start of study treatment up to 30 days after the last dose

Population: Safety Analysis Set (SAF) was comprised of all randomized participants who received at least one dose of study medication (sorafenib, placebo or capecitabine). Participants were analyzed as treated.

Hematological (anemia, hemoglobin, international normalized ratio \[INR\], lymphocyte, neutrophil, platelet, white blood cell \[WBC\]), biochemical (ALT \[alanine aminotransferase\], AST \[aspartate aminotransferase\], GGT \[gamma-glutamyl-transferase\], lipase, hypoalbuminemia, hypocalcemia, hyperglycemia, hyperuricemia) evaluations were done. Common terminology criteria for adverse events (CTCAE) version 4-Grade 3: Severe or medically significant; hospitalization or prolongation of hospitalization and CTCAE version 4-Grade 4: life-threatening consequences; urgent intervention were indicated.

Outcome measures

Outcome measures
Measure	Sorafenib (Nexavar, BAY43-9006) + Capecitabine n=260 Participants Sorafenib tablets were administered orally continuously at a total daily dose of 600 mg (200 mg in the morning, 400 mg in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and sorafenib dose to a total daily dose of 800 mg for that participant.	Placebo + Capecitabine n=267 Participants Placebo tablets matching with sorafenib were administered orally continuously (1 tablet in the morning, 2 tablets in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a participant, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that participant.
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Neutrophil count decreased (grade 3)	11 Participants	19 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities GGT increased (grade 3)	22 Participants	21 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Lipase increased (grade 3)	19 Participants	12 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Serum amylase increased (grade 3)	8 Participants	4 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Alkaline phosphatase increased (grade 3)	12 Participants	13 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Bilirubin increased (grade 3)	9 Participants	1 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Hypoalbuminemia (grade 3)	4 Participants	2 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Hypocalcemia (grade 3)	9 Participants	6 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Hypokalemia (grade 3)	20 Participants	11 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Anemia (grade 3)	12 Participants	7 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Hemoglobin increased (grade 3)	0 Participants	3 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities INR increased (grade 3)	9 Participants	9 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Lymphocyte count decreased (grade 3)	20 Participants	17 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Platelet count decreased (grade 3)	6 Participants	2 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities WBC decreased (grade 3)	15 Participants	13 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities ALT increased (grade 3)	4 Participants	5 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities AST increased (grade 3)	10 Participants	5 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Hyponatremia (grade 3)	9 Participants	7 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Hypophosphatemia (grade 3)	47 Participants	15 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Hyperglycemia (grade 3)	9 Participants	10 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Lymphocyte count decreased (grade 4)	3 Participants	2 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Neutrophil count decreased (grade 4)	7 Participants	7 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Platelet count decreased (grade 4)	1 Participants	7 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities WBC decreased (grade 4)	2 Participants	3 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities ALT increased (grade 4)	3 Participants	0 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities GGT increased (grade 4)	6 Participants	2 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Lipase increased (grade 4)	5 Participants	1 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Hypokalemia (grade 4)	2 Participants	4 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Hyponatremia (grade 4)	4 Participants	0 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Hypophosphatemia (grade 4)	5 Participants	0 Participants
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities Hyperuricemia (grade 4)	5 Participants	0 Participants

Adverse Events

Sorafenib (Nexavar, BAY43-9006) + Capecitabine

Serious events: 80 serious events

Other events: 256 other events

Deaths: 0 deaths

Placebo + Capecitabine

Serious events: 71 serious events

Other events: 248 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Therapeutic Area Head

BAYER

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Bayer will have up to 30/45 days to review publications, and may request an additional publication delay of up to 60 days to allow for filing a Patent Application (if applicable). No publication of single center data should be done prior to publication of multi-center data.
Publication restrictions are in place

Restriction type: OTHER

Measure	Sorafenib (Nexavar, BAY43-9006) + Capecitabine n=260 participants at risk Sorafenib tablets were administered orally continuously at a total daily dose of 600 mg (200 mg in the morning, 400 mg in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a subject, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and sorafenib dose to a total daily dose of 800 mg for that subject.	Placebo + Capecitabine n=267 participants at risk Placebo tablets matching with sorafenib were administered orally continuously (1 tablet in the morning, 2 tablets in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m\^2 (1,000 mg/m\^2 twice daily, 12 hours apart). If tolerability criteria were met for a subject, capecitabine dose was escalated to 2,500 mg/m\^2 total daily dose (1,250 mg/m\^2 twice daily) and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that subject.
Blood and lymphatic system disorders Anaemia	11.9% 31/260 • Number of events 37 • From start of study drug administration until 30 days after the last dose of study medication intake.	12.0% 32/267 • Number of events 37 • From start of study drug administration until 30 days after the last dose of study medication intake.
Blood and lymphatic system disorders Neutropenia	4.6% 12/260 • Number of events 22 • From start of study drug administration until 30 days after the last dose of study medication intake.	9.0% 24/267 • Number of events 46 • From start of study drug administration until 30 days after the last dose of study medication intake.
Eye disorders Lacrimation increased	0.00% 0/260 • From start of study drug administration until 30 days after the last dose of study medication intake.	6.0% 16/267 • Number of events 21 • From start of study drug administration until 30 days after the last dose of study medication intake.
Gastrointestinal disorders Abdominal pain	12.7% 33/260 • Number of events 40 • From start of study drug administration until 30 days after the last dose of study medication intake.	10.5% 28/267 • Number of events 41 • From start of study drug administration until 30 days after the last dose of study medication intake.
Gastrointestinal disorders Abdominal pain upper	13.5% 35/260 • Number of events 44 • From start of study drug administration until 30 days after the last dose of study medication intake.	7.1% 19/267 • Number of events 22 • From start of study drug administration until 30 days after the last dose of study medication intake.
Gastrointestinal disorders Constipation	20.4% 53/260 • Number of events 67 • From start of study drug administration until 30 days after the last dose of study medication intake.	12.4% 33/267 • Number of events 36 • From start of study drug administration until 30 days after the last dose of study medication intake.
Gastrointestinal disorders Diarrhoea	47.3% 123/260 • Number of events 291 • From start of study drug administration until 30 days after the last dose of study medication intake.	36.7% 98/267 • Number of events 190 • From start of study drug administration until 30 days after the last dose of study medication intake.
Gastrointestinal disorders Dyspepsia	6.2% 16/260 • Number of events 19 • From start of study drug administration until 30 days after the last dose of study medication intake.	9.4% 25/267 • Number of events 31 • From start of study drug administration until 30 days after the last dose of study medication intake.
Gastrointestinal disorders Nausea	38.8% 101/260 • Number of events 166 • From start of study drug administration until 30 days after the last dose of study medication intake.	36.3% 97/267 • Number of events 150 • From start of study drug administration until 30 days after the last dose of study medication intake.
Gastrointestinal disorders Stomatitis	17.3% 45/260 • Number of events 54 • From start of study drug administration until 30 days after the last dose of study medication intake.	9.0% 24/267 • Number of events 29 • From start of study drug administration until 30 days after the last dose of study medication intake.
Gastrointestinal disorders Vomiting	25.0% 65/260 • Number of events 118 • From start of study drug administration until 30 days after the last dose of study medication intake.	19.9% 53/267 • Number of events 83 • From start of study drug administration until 30 days after the last dose of study medication intake.
General disorders Asthenia	18.8% 49/260 • Number of events 67 • From start of study drug administration until 30 days after the last dose of study medication intake.	19.1% 51/267 • Number of events 69 • From start of study drug administration until 30 days after the last dose of study medication intake.
General disorders Fatigue	30.4% 79/260 • Number of events 101 • From start of study drug administration until 30 days after the last dose of study medication intake.	30.3% 81/267 • Number of events 102 • From start of study drug administration until 30 days after the last dose of study medication intake.
General disorders Influenza like illness	1.9% 5/260 • Number of events 9 • From start of study drug administration until 30 days after the last dose of study medication intake.	5.6% 15/267 • Number of events 19 • From start of study drug administration until 30 days after the last dose of study medication intake.
General disorders Mucosal inflammation	15.0% 39/260 • Number of events 49 • From start of study drug administration until 30 days after the last dose of study medication intake.	7.1% 19/267 • Number of events 20 • From start of study drug administration until 30 days after the last dose of study medication intake.
General disorders Oedema peripheral	3.5% 9/260 • Number of events 10 • From start of study drug administration until 30 days after the last dose of study medication intake.	8.6% 23/267 • Number of events 29 • From start of study drug administration until 30 days after the last dose of study medication intake.
General disorders Pyrexia	10.8% 28/260 • Number of events 31 • From start of study drug administration until 30 days after the last dose of study medication intake.	12.0% 32/267 • Number of events 39 • From start of study drug administration until 30 days after the last dose of study medication intake.
Infections and infestations Nasopharyngitis	9.2% 24/260 • Number of events 35 • From start of study drug administration until 30 days after the last dose of study medication intake.	8.6% 23/267 • Number of events 28 • From start of study drug administration until 30 days after the last dose of study medication intake.
Infections and infestations Upper respiratory tract infection	5.8% 15/260 • Number of events 15 • From start of study drug administration until 30 days after the last dose of study medication intake.	4.1% 11/267 • Number of events 12 • From start of study drug administration until 30 days after the last dose of study medication intake.
Infections and infestations Urinary tract infection	6.2% 16/260 • Number of events 21 • From start of study drug administration until 30 days after the last dose of study medication intake.	5.6% 15/267 • Number of events 16 • From start of study drug administration until 30 days after the last dose of study medication intake.
Investigations Alanine aminotransferase increased	10.4% 27/260 • Number of events 34 • From start of study drug administration until 30 days after the last dose of study medication intake.	7.9% 21/267 • Number of events 24 • From start of study drug administration until 30 days after the last dose of study medication intake.
Investigations Aspartate aminotransferase increased	10.4% 27/260 • Number of events 32 • From start of study drug administration until 30 days after the last dose of study medication intake.	8.6% 23/267 • Number of events 26 • From start of study drug administration until 30 days after the last dose of study medication intake.
Investigations Blood bilirubin increased	7.3% 19/260 • Number of events 27 • From start of study drug administration until 30 days after the last dose of study medication intake.	6.4% 17/267 • Number of events 26 • From start of study drug administration until 30 days after the last dose of study medication intake.
Investigations Gamma-glutamyltransferase increased	5.4% 14/260 • Number of events 14 • From start of study drug administration until 30 days after the last dose of study medication intake.	1.5% 4/267 • Number of events 4 • From start of study drug administration until 30 days after the last dose of study medication intake.
Investigations Lipase increased	5.0% 13/260 • Number of events 15 • From start of study drug administration until 30 days after the last dose of study medication intake.	1.9% 5/267 • Number of events 5 • From start of study drug administration until 30 days after the last dose of study medication intake.
Investigations Neutrophil count decreased	5.4% 14/260 • Number of events 27 • From start of study drug administration until 30 days after the last dose of study medication intake.	3.7% 10/267 • Number of events 22 • From start of study drug administration until 30 days after the last dose of study medication intake.
Investigations Weight decreased	10.8% 28/260 • Number of events 28 • From start of study drug administration until 30 days after the last dose of study medication intake.	4.5% 12/267 • Number of events 13 • From start of study drug administration until 30 days after the last dose of study medication intake.
Investigations White blood cell count decreased	6.5% 17/260 • Number of events 23 • From start of study drug administration until 30 days after the last dose of study medication intake.	4.5% 12/267 • Number of events 23 • From start of study drug administration until 30 days after the last dose of study medication intake.
Metabolism and nutrition disorders Hypokalaemia	8.5% 22/260 • Number of events 24 • From start of study drug administration until 30 days after the last dose of study medication intake.	5.6% 15/267 • Number of events 19 • From start of study drug administration until 30 days after the last dose of study medication intake.
Metabolism and nutrition disorders Hypophosphataemia	6.2% 16/260 • Number of events 22 • From start of study drug administration until 30 days after the last dose of study medication intake.	1.5% 4/267 • Number of events 5 • From start of study drug administration until 30 days after the last dose of study medication intake.
Metabolism and nutrition disorders Decreased appetite	20.4% 53/260 • Number of events 63 • From start of study drug administration until 30 days after the last dose of study medication intake.	14.2% 38/267 • Number of events 40 • From start of study drug administration until 30 days after the last dose of study medication intake.
Musculoskeletal and connective tissue disorders Arthralgia	13.5% 35/260 • Number of events 54 • From start of study drug administration until 30 days after the last dose of study medication intake.	10.1% 27/267 • Number of events 33 • From start of study drug administration until 30 days after the last dose of study medication intake.
Musculoskeletal and connective tissue disorders Back pain	12.7% 33/260 • Number of events 39 • From start of study drug administration until 30 days after the last dose of study medication intake.	12.4% 33/267 • Number of events 34 • From start of study drug administration until 30 days after the last dose of study medication intake.
Musculoskeletal and connective tissue disorders Muscle spasms	6.5% 17/260 • Number of events 24 • From start of study drug administration until 30 days after the last dose of study medication intake.	2.2% 6/267 • Number of events 6 • From start of study drug administration until 30 days after the last dose of study medication intake.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	3.5% 9/260 • Number of events 9 • From start of study drug administration until 30 days after the last dose of study medication intake.	6.4% 17/267 • Number of events 21 • From start of study drug administration until 30 days after the last dose of study medication intake.
Musculoskeletal and connective tissue disorders Pain in extremity	8.8% 23/260 • Number of events 32 • From start of study drug administration until 30 days after the last dose of study medication intake.	7.9% 21/267 • Number of events 28 • From start of study drug administration until 30 days after the last dose of study medication intake.
Nervous system disorders Dizziness	8.1% 21/260 • Number of events 26 • From start of study drug administration until 30 days after the last dose of study medication intake.	8.2% 22/267 • Number of events 26 • From start of study drug administration until 30 days after the last dose of study medication intake.
Nervous system disorders Dysgeusia	4.6% 12/260 • Number of events 13 • From start of study drug administration until 30 days after the last dose of study medication intake.	7.5% 20/267 • Number of events 20 • From start of study drug administration until 30 days after the last dose of study medication intake.
Nervous system disorders Headache	13.5% 35/260 • Number of events 49 • From start of study drug administration until 30 days after the last dose of study medication intake.	13.5% 36/267 • Number of events 45 • From start of study drug administration until 30 days after the last dose of study medication intake.
Psychiatric disorders Anxiety	7.3% 19/260 • Number of events 19 • From start of study drug administration until 30 days after the last dose of study medication intake.	4.5% 12/267 • Number of events 12 • From start of study drug administration until 30 days after the last dose of study medication intake.
Psychiatric disorders Insomnia	6.2% 16/260 • Number of events 16 • From start of study drug administration until 30 days after the last dose of study medication intake.	4.5% 12/267 • Number of events 12 • From start of study drug administration until 30 days after the last dose of study medication intake.
Respiratory, thoracic and mediastinal disorders Cough	9.6% 25/260 • Number of events 25 • From start of study drug administration until 30 days after the last dose of study medication intake.	8.6% 23/267 • Number of events 25 • From start of study drug administration until 30 days after the last dose of study medication intake.
Respiratory, thoracic and mediastinal disorders Dyspnoea	12.3% 32/260 • Number of events 34 • From start of study drug administration until 30 days after the last dose of study medication intake.	15.4% 41/267 • Number of events 47 • From start of study drug administration until 30 days after the last dose of study medication intake.
Skin and subcutaneous tissue disorders Alopecia	16.9% 44/260 • Number of events 49 • From start of study drug administration until 30 days after the last dose of study medication intake.	2.2% 6/267 • Number of events 6 • From start of study drug administration until 30 days after the last dose of study medication intake.
Skin and subcutaneous tissue disorders Dry skin	7.3% 19/260 • Number of events 23 • From start of study drug administration until 30 days after the last dose of study medication intake.	6.4% 17/267 • Number of events 19 • From start of study drug administration until 30 days after the last dose of study medication intake.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	79.2% 206/260 • Number of events 288 • From start of study drug administration until 30 days after the last dose of study medication intake.	59.2% 158/267 • Number of events 228 • From start of study drug administration until 30 days after the last dose of study medication intake.
Skin and subcutaneous tissue disorders Rash	18.5% 48/260 • Number of events 58 • From start of study drug administration until 30 days after the last dose of study medication intake.	8.2% 22/267 • Number of events 29 • From start of study drug administration until 30 days after the last dose of study medication intake.
Vascular disorders Hypertension	26.5% 69/260 • Number of events 92 • From start of study drug administration until 30 days after the last dose of study medication intake.	6.0% 16/267 • Number of events 21 • From start of study drug administration until 30 days after the last dose of study medication intake.