Breast Cancer
Conditions
Keywords
Breast Cancer, HER2-neu
Brief summary
The objective of this phase-III trial is to compare the efficacy and safety of sorafenib in combination with capecitabine versus capecitabine in combination with placebo in the treatment of subjects with locally advanced or metastatic HER2-negative breast cancer who are resistant to or have failed prior taxane and an anthracycline or for whom further anthracycline therapy is not indicated. After signing consent there can be up to 28 days before starting the treatment during which time a number of tests will be carried out which will include tumor evaluations and medical history. The following tests and evaluations will have to be done within 7 days of the start of treatment,on Day 1 of every cycle and at the end of study: Electrocardiogram, blood tests, patient quality of life questionnaires and a complete physical exam and vital signs. Treatment will be given in 21 day cycles with sorafenib/placebo to be taken every day for 21 days and capecitabine to be taken for the first 14 days. Patients will come in weekly for the first 6 weeks and then on Day1 for every cycle after the first 2 cycles. During the weekly visits the subjects will be check for any side effects and blood draws will happen for the study on Day 1 of each cycle. Subjects will be followed for overall survival.
Detailed description
Research summary (NRES, UK): Breast cancer is the most commonly diagnosed cancer in women and the leading cause of cancer-related death among women worldwide. However, despite advances in treatment of the early-stage disease, about 25-40% of patients will develop recurrence or spread to other parts of the body that is largely incurable. The average survival of patients with breast cancer that has spread to other parts of the body (metastasis) is 2 to 3 years after diagnosis, and although a number of treatment options are available, including various chemotherapy agents, no single standard of care exists. The study drug (Sorafenib) works by inhibiting certain pathways in the body that contribute to tumour growth and the formation of new blood vessels (angiogenesis). Angiogenesis plays an important role in the development, transformation and spread of breast cancer. Capecitabine is an approved chemotherapy drug for patients whose breast cancer has spread to other parts of the body (metastatic) and is not responsive to other classes of chemotherapy drugs. Data from a Phase IIb clinical study suggests that there is a role for the combination of Sorafenib and Capecitabine to treat locally advanced or metastatic breast cancer. Patients in this confirmatory Phase III study will be randomly assigned to receive either: * Capecitabine + Sorafenib * Capecitabine + placebo (dummy medication with no active drug) Participants will continue to receive treatments until there is radiographic or clinical progression of disease, side effects which require them to withdraw, pregnancy, protocol non-compliance or withdrawal of consent. Therefore length of participation will vary for individuals. This study is expected to close 31 March 2013. This is a multicentre study which will take place across Europe, North and South America, Asia, Australia and South Africa. It is anticipated that approximately 519 participants will be recruited worldwide.
Interventions
DRUGSorafenib (Nexavar, BAY43-9006)
Capecitabine was administered orally at a dose of 1,000 milligram per square meter (mg/m\^2) twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle. Sorafenib was administered orally at a dose of 600 mg (200 mg in the morning, 400 mg in the evening) daily, continuously (that is, Days 1 to 21, inclusive). A treatment cycle consisted of 21 days. If tolerability criteria were met for a subject, capecitabine dose was escalated to 1,250 mg/m\^2 twice daily and sorafenib dose to a total daily dose of 800 mg for that subject.
DRUGPlacebo
Capecitabine was administered orally at a dose of 1,000 mg/m\^2 twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle. Placebo matching to sorafenib was administered orally, 3 tablets (1 tablet in the morning, 2 tablets in the evening) daily, continuously (that is, Days 1 to 21, inclusive). A treatment cycle consisted of 21 days. If tolerability criteria were met for a subject, capecitabine dose was escalated to 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.
DRUGCapecitabine
Capecitabine was administered orally at a dose of 1,000 milligram per square meter (mg/m\^2) twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle.days. If tolerability criteria were met for a subject, capecitabine dose was escalated to 1,250 mg/m\^2 twice daily,
Sponsors
Onyx Therapeutics, Inc.
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age is \>=18 years * Subject has histologically or cytologically confirmed HER2-negative adenocarcinoma of the breast. HER2 status should be determined by an accredited laboratory * Subject has locally advanced or metastatic disease; locally advanced disease must not be amenable to resection with curative intent. Must have measurable or non-measurable disease (according to RECIST \[Response Evaluation Criteria for Solid Tumors\] 1.1) * All computer tomography (CT; with contrast) and magnetic resonance imaging (MRI) used to document disease must have been done \<= 4 weeks before randomization. Bone scans (if clinically indicated) must have been done \<= 12 weeks prior to randomization * Subject must have received up to two prior chemotherapy regimens (adjuvant/neo-adjuvant treatments are considered one regimen), and no more than one prior regimen for advanced and/or metastatic disease. Chemotherapy regimens include both targeted and biologic therapy * Prior regimens must have included an anthracycline (eg, doxorubicin, epirubicin) and a taxane (eg, paclitaxel, docetaxel), either in combination or in separate regimens, in either the neo-adjuvant/adjuvant or the metastatic setting or both, as either monotherapy or as part of a combination with another agent. Sequential regimens will count as a single regimen; multiple neo-adjuvant / adjuvant regimens will count as a single regimen * Subjects are either resistant to or have failed prior taxane and anthracycline OR Resistant to or have failed prior taxane AND for whom further anthracycline therapy is not indicated (for example, intolerance or cumulative doses of doxorubicin or doxorubicin equivalents \[for example, epirubicin) * Subjects who relapse beyond 12 months after the last taxane or anthracycline dose given in the adjuvant, neo-adjuvant, or metastatic setting are eligible. Further therapy with the agent(s) for a subsequent regimen must have been considered and ruled out, for example due to prior toxicity or intolerance, or based on the local standard of practice * Prior experimental chemotherapy treatment is allowed, provided it is given in combination with at least one drug approved for the treatment of breast cancer (excluding drugs that target VEGF \[Vascular Endothelial Growth Factor\] or VEGFR \[Vascular Endothelial Growth Factor Receptor\], eg, bevacizumab, brivanib, sunitinib, vatalinib). * Prior hormonal therapy for locally advanced or metastatic breast cancer is allowed. Subjects who are refractory to hormonal therapy are allowed. * Prior neo-adjuvant or adjuvant chemotherapy is allowed. * Subject must have discontinued prior chemotherapy (including both targeted and biologic therapies), prior therapeutic radiation therapy, or prior hormonal therapy for locally advanced or metastatic disease \>= 4 weeks (28 days) before randomization. Start of study treatment is allowed within less than 28 days of the prior therapy provided that 5 half-lives of the prior treatment drug(s) have elapsed * ECOG (Eastern Cooperative Oncology Group) performance status 0 or 1 * Adequate bone marrow, liver and renal function within 7 days prior to randomization * All acute toxic effects of any prior treatment have resolved to NCI-CTCAE (National Cancer Institute-Common Terminology Criteria for Adverse Events) v4.0 Grade 1 or less * Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to randomization * Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the ICF (Informed Consent Form) until at least 30 days after the last dose of study drug. * Subject must be able to swallow and retain oral medication
Exclusion criteria
* HER2 positive breast cancer * Unknown hormone receptor status (estrogen and progesterone receptor). * Subjects with bilateral breast cancer or a history of two distinct breast cancers. * Subjects with inflammatory breast carcinoma. * Subjects who have received no prior taxane and anthracycline for the treatment of breast cancer (either in adjuvant, neo-adjuvant or metastatic setting). * Prior use of sorafenib or capecitabine * Subjects considered by the treating investigator to be appropriate candidates for hormonal therapy as current treatment for locally advanced/metastatic breast cancer * Subjects with locally advanced disease who are considered by the treating investigator to be appropriate candidates for radiation therapy as current treatment for locally advanced breast cancer * Subjects with active brain metastases or leptomeningeal disease. * Subjects with seizure disorder requiring medication. * Radiation to any lesions \<= 4 weeks prior to randomization. Palliative radiation to bone metastasis for pain control is permitted with provisions * Major surgery, open biopsy, or significant traumatic injury \<= 4 weeks * Evidence or history of bleeding diathesis or coagulopathy. Uncontrolled hypertension, active or clinically significant cardiac disease. Subject with thrombotic, embolic, venus or arterial events * Subjects with any hemorrhage/bleeding event of NCI-CTCAE v4.0 Grade 3 or higher within 4 weeks before randomization * Subjects with an infection of NCI-CTCAE v4.0 \> Grade 2 * Subjects with a history of human immunodeficiency virus infection or current chronic or active hepatitis B or C infection. * Subjects who have used strong CYP3A4 inducers (eg, phenytoin, carbamazepine, phenobarbital, St. John's Wort \[Hypericum perforatum\], dexamethasone at a dose of greater than 16 mg daily, or rifampin \[rifampicin\], and/or rifabutin) within 28 days before randomization. * Subjects with any previously untreated or concurrent cancer that is distinct in primary site or histology from breast cancer * Subjects with a history DHPD (Dihydropyrimidine dehydrogenase) reaction to fluropyrimidine or history of known or suspected allergy or hypersensitivity to any of the study drugs * Presence of a non-healing wound, non-healing ulcer, or bone fracture * Women pregnant or breast feeding * Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Assessed by the Independent Review Panel According to Response Evaluation Criteria for Solid Tumors (RECIST) 1.1 | From randomization of the first participant until approximately 3 years or until disease radiological progression | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization of the first participant until approximately 3 years later | 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. |
| Time to Progression (TTP) by Central Review | From randomization of the first participant until approximately 3 years later or until disease radiological progression | 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. |
| Objective Response Rate (ORR) by Central Review | From randomization of the first participant until approximately 3 years later or until disease radiological progression | 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. |
| Disease Control Rate (DCR) by Central Review | From randomization of the first participant until approximately 3 years later or until disease radiological progression | 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. |
| Duration of Response (DOR) by Central Reader | From randomization of the first participant until approximately 3 years later or until disease radiological progression | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Patient Reported Outcomes: Functional Assessment of Cancer Therapy-Breast Symptom Index (8 Item) (FBSI-8) | 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) | 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'. |
| Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Index Score | 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) | 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'. |
| Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Visual Analogue Scale (VAS) Score | 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) | 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'. |
| Maximum Observed Drug Concentration (Cmax) of Capecitabine and 5-fluorouracil | Pre-dose and 0.5, 1, 2, and 4 hours after capecitabine dosing at Cycle 2, Day 14 | 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. |
| Area Under Curve From Time Zero to Last Quantifiable Concentration (AUC[0-tlast]) of Capecitabine and 5-fluorouracil | Pre-dose and 0.5, 1, 2, and 4 hours after capecitabine dosing at Cycle 2, Day 14 | 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. |
| Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | From the start of study treatment up to 30 days after the last dose | 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. |
Countries
Argentina, Australia, Austria, Belgium, Canada, China, Czechia, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Japan, Poland, Puerto Rico, Russia, South Africa, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 266 |
| 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. | 271 |
| Total | 537 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 58 | 21 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Disease progression/recurrence/relapse | 181 | 223 |
| Overall Study | Investi. decision not protocol driven | 5 | 6 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Non-compliant with study medication | 3 | 2 |
| Overall Study | Protocol Violation | 2 | 3 |
| Overall Study | Randomized but not treated | 6 | 4 |
| Overall Study | Switch to commercial drug | 0 | 1 |
| Overall Study | Withdrawal by Subject | 11 | 9 |
Baseline characteristics
| Characteristic | Total | Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Placebo + Capecitabine |
|---|---|---|---|
| Age, Continuous | 53.9 years STANDARD_DEVIATION 10.6 | 53.3 years STANDARD_DEVIATION 10.2 | 54.4 years STANDARD_DEVIATION 10.9 |
| Eastern Cooperative Oncology Group (ECOG) ECOG status=0 | 313 Participants | 152 Participants | 161 Participants |
| Eastern Cooperative Oncology Group (ECOG) ECOG status=1 | 224 Participants | 114 Participants | 110 Participants |
| Eastern Cooperative Oncology Group (ECOG) ECOG status=2 | 0 Participants | 0 Participants | 0 Participants |
| Eastern Cooperative Oncology Group (ECOG) ECOG status=3 | 0 Participants | 0 Participants | 0 Participants |
| Eastern Cooperative Oncology Group (ECOG) ECOG status=4 | 0 Participants | 0 Participants | 0 Participants |
| Hormone Receptor Status Negative | 167 Participants | 83 Participants | 84 Participants |
| Hormone Receptor Status Positive | 370 Participants | 183 Participants | 187 Participants |
| Number of Prior Chemotherapies for Metastatic Disease Prior chemotherapies=0 | 232 Participants | 114 Participants | 118 Participants |
| Number of Prior Chemotherapies for Metastatic Disease Prior chemotherapies=1 | 305 Participants | 152 Participants | 153 Participants |
| Race/Ethnicity, Customized Asian | 100 Participants | 50 Participants | 50 Participants |
| Race/Ethnicity, Customized Black | 11 Participants | 7 Participants | 4 Participants |
| Race/Ethnicity, Customized Hispanic | 9 Participants | 4 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 417 Participants | 205 Participants | 212 Participants |
| Region of Enrollment Europe | 334 Participants | 166 Participants | 168 Participants |
| Region of Enrollment North America | 49 Participants | 23 Participants | 26 Participants |
| Region of Enrollment Other | 154 Participants | 77 Participants | 77 Participants |
| Sex: Female, Male Female | 533 Participants | 265 Participants | 268 Participants |
| Sex: Female, Male Male | 4 Participants | 1 Participants | 3 Participants |
| Visceral Disease at Baseline Missing | 2 Participants | 1 Participants | 1 Participants |
| Visceral Disease at Baseline No | 123 Participants | 66 Participants | 57 Participants |
| Visceral Disease at Baseline Yes | 412 Participants | 199 Participants | 213 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 256 / 260 | 248 / 267 |
| serious Total, serious adverse events | 80 / 260 | 71 / 267 |
Outcome results
Primary
Progression-free Survival (PFS) Assessed by the Independent Review Panel According to Response Evaluation Criteria for Solid Tumors (RECIST) 1.1
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Progression-free Survival (PFS) Assessed by the Independent Review Panel According to Response Evaluation Criteria for Solid Tumors (RECIST) 1.1 | 166 days |
| Placebo + Capecitabine | Progression-free Survival (PFS) Assessed by the Independent Review Panel According to Response Evaluation Criteria for Solid Tumors (RECIST) 1.1 | 165 days |
Comparison: PFS was compared using a stratified log-rank test with a one-sided alpha of 0.005, stratified by region, hormone receptor status, number of previous chemotherapies for metastatic disease. The hazard ratio (sorafenib + capecitabine / placebo + capecitabine) and its 95 percent (%) CIs were calculated using the Cox model, stratified by the above factors. A Hazard ratio of less than (\<) 1 indicates superiority of Sorafenib + Capecitabine over Placebo + Capecitabine.p-value: =0.40561895% CI: [0.779, 1.217]Log Rank
Secondary
Disease Control Rate (DCR) by Central Review
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.
Time frame: From randomization of the first participant until approximately 3 years later or until disease radiological progression
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Disease Control Rate (DCR) by Central Review | 60.5 percentage (%) of participants |
| Placebo + Capecitabine | Disease Control Rate (DCR) by Central Review | 58.3 percentage (%) of participants |
Comparison: DCR and 95% CI based on general association Cochran-Mantel-Haenszel statistic with one-sided alpha of 0.025 stratified by number of prior chemotherapies for metastatic disease, hormone receptor status, and region. Difference = Placebo + Capecitabine - Sorafenib + Capecitabine.p-value: =0.28467495% CI: [-10.4, 5.72]Cochran-Mantel-Haenszel
Secondary
Duration of Response (DOR) by Central Reader
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Duration of Response (DOR) by Central Reader | 313 days |
| Placebo + Capecitabine | Duration of Response (DOR) by Central Reader | 290 days |
Secondary
Objective Response Rate (ORR) by Central Review
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.
Time frame: From randomization of the first participant until approximately 3 years later or until disease radiological progression
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Objective Response Rate (ORR) by Central Review | 13.5 Percentage (%) of participants |
| Placebo + Capecitabine | Objective Response Rate (ORR) by Central Review | 15.5 Percentage (%) of participants |
Comparison: ORR and 95% CI based on Cochran Mantel-Haenszel Test stratified by region, hormone receptor status, number of previous chemotherapies for metastatic disease. Difference = (Placebo + Capecitabine) - (Sorafenib + Capecitabine).p-value: =0.25741295% CI: [-3.9, 7.77]Cochran-Mantel-Haenszel
Secondary
Overall Survival (OS)
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.
Time frame: From randomization of the first participant until approximately 3 years later
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Overall Survival (OS) | 575 days |
| Placebo + Capecitabine | Overall Survival (OS) | 616 days |
Comparison: At the time of PFS final analysis, it was OS interim analysis (IA) with 285 total death events. According to protocol specified O'Brien-Fleming type alpha spending function and 285 death events at IA, the prespecified alpha for this analysis was 0.0075 (one-sided). A Hazard ratio \< 1 indicates superiority of Sorafenib+Capecitabine over Placebo+Capecitabine.p-value: =0.93008895% CI: [0.943, 1.513]Log Rank
Secondary
Time to Progression (TTP) by Central Review
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.
Time frame: From randomization of the first participant until approximately 3 years later or until disease radiological progression
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Time to Progression (TTP) by Central Review | 168 days |
| Placebo + Capecitabine | Time to Progression (TTP) by Central Review | 165 days |
Comparison: TTP was compared using a stratified log-rank test with a one-sided alpha of 0.025, stratified by region, hormone receptor status, number of previous chemotherapies for metastatic disease. A Hazard ratio \<1 indicates superiority of Sorafenib+Capecitabine over Placebo+Capecitabine.p-value: =0.210595% CI: [0.723, 1.146]Log Rank
Other Pre-specified
Area Under Curve From Time Zero to Last Quantifiable Concentration (AUC[0-tlast]) of Capecitabine and 5-fluorouracil
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.
Time frame: Pre-dose and 0.5, 1, 2, and 4 hours after capecitabine dosing at Cycle 2, Day 14
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | 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 |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | 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 |
| Placebo + Capecitabine | Area Under Curve From Time Zero to Last Quantifiable Concentration (AUC[0-tlast]) of Capecitabine and 5-fluorouracil | 5-fluorouracil | 0.557 milligram*hour per liter | Geometric Coefficient of Variation 47 |
| Placebo + Capecitabine | Area Under Curve From Time Zero to Last Quantifiable Concentration (AUC[0-tlast]) of Capecitabine and 5-fluorouracil | Capecitabine | 5.13 milligram*hour per liter | Geometric Coefficient of Variation 48 |
Comparison: Statistical analysis for AUC(0-tlast): 5-fluorouracil90% CI: [0.95, 1.3]
Comparison: Statistical analysis for AUC(0-tlast): Capecitabine90% CI: [1.22, 1.58]
Other Pre-specified
Maximum Observed Drug Concentration (Cmax) of Capecitabine and 5-fluorouracil
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.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Maximum Observed Drug Concentration (Cmax) of Capecitabine and 5-fluorouracil | Capecitabine | 6.05 milligram per liter | Geometric Coefficient of Variation 79 |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Maximum Observed Drug Concentration (Cmax) of Capecitabine and 5-fluorouracil | 5-fluorouracil | 0.434 milligram per liter | Geometric Coefficient of Variation 105 |
| Placebo + Capecitabine | Maximum Observed Drug Concentration (Cmax) of Capecitabine and 5-fluorouracil | Capecitabine | 4.68 milligram per liter | Geometric Coefficient of Variation 72 |
| Placebo + Capecitabine | Maximum Observed Drug Concentration (Cmax) of Capecitabine and 5-fluorouracil | 5-fluorouracil | 0.382 milligram per liter | Geometric Coefficient of Variation 67 |
Comparison: Statistical analysis for Cmax: 5-fluorouracil90% CI: [0.92, 1.4]
Comparison: Statistical analysis for Cmax: Capecitabine90% CI: [1.07, 1.56]
Other Pre-specified
Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Anemia (grade 3) | 12 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hemoglobin increased (grade 3) | 0 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | INR increased (grade 3) | 9 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Lymphocyte count decreased (grade 3) | 20 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Neutrophil count decreased (grade 3) | 11 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Platelet count decreased (grade 3) | 6 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | WBC decreased (grade 3) | 15 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | ALT increased (grade 3) | 4 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | AST increased (grade 3) | 10 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Alkaline phosphatase increased (grade 3) | 12 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Bilirubin increased (grade 3) | 9 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | GGT increased (grade 3) | 22 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Lipase increased (grade 3) | 19 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Serum amylase increased (grade 3) | 8 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hypoalbuminemia (grade 3) | 4 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hypocalcemia (grade 3) | 9 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hypokalemia (grade 3) | 20 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hyponatremia (grade 3) | 9 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hypophosphatemia (grade 3) | 47 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hyperglycemia (grade 3) | 9 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Lymphocyte count decreased (grade 4) | 3 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Neutrophil count decreased (grade 4) | 7 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Platelet count decreased (grade 4) | 1 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | WBC decreased (grade 4) | 2 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | ALT increased (grade 4) | 3 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | GGT increased (grade 4) | 6 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Lipase increased (grade 4) | 5 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hypokalemia (grade 4) | 2 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hyponatremia (grade 4) | 4 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hypophosphatemia (grade 4) | 5 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hyperuricemia (grade 4) | 5 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hypocalcemia (grade 3) | 6 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Anemia (grade 3) | 7 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | WBC decreased (grade 4) | 3 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hemoglobin increased (grade 3) | 3 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hypokalemia (grade 3) | 11 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | INR increased (grade 3) | 9 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hypokalemia (grade 4) | 4 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Lymphocyte count decreased (grade 3) | 17 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hyponatremia (grade 3) | 7 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Neutrophil count decreased (grade 3) | 19 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | ALT increased (grade 4) | 0 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Platelet count decreased (grade 3) | 2 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hypophosphatemia (grade 3) | 15 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | WBC decreased (grade 3) | 13 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hypophosphatemia (grade 4) | 0 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | ALT increased (grade 3) | 5 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hyperglycemia (grade 3) | 10 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | AST increased (grade 3) | 5 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | GGT increased (grade 4) | 2 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Alkaline phosphatase increased (grade 3) | 13 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Lymphocyte count decreased (grade 4) | 2 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Bilirubin increased (grade 3) | 1 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hyponatremia (grade 4) | 0 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | GGT increased (grade 3) | 21 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Neutrophil count decreased (grade 4) | 7 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Lipase increased (grade 3) | 12 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Lipase increased (grade 4) | 1 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Serum amylase increased (grade 3) | 4 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Platelet count decreased (grade 4) | 7 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hypoalbuminemia (grade 3) | 2 Participants |
| Placebo + Capecitabine | Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities | Hyperuricemia (grade 4) | 0 Participants |
Other Pre-specified
Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Index Score
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'.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Index Score | 0.665 Scores on a scale |
| Placebo + Capecitabine | Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Index Score | 0.69 Scores on a scale |
Comparison: Estimate of Difference (least squares mean \[LSM\] difference) = (Sorafenib + Capecitabine) - (Placebo + Capecitabine). The difference between the two treatment groups was evaluated with an analysis of covariance model using the baseline score and the same stratification factors as used for randomization (IVRS) as covariates.95% CI: [-0.053, 0.002]
Other Pre-specified
Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Visual Analogue Scale (VAS) Score
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'.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Visual Analogue Scale (VAS) Score | 67.532 Scores on a scale |
| Placebo + Capecitabine | Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Visual Analogue Scale (VAS) Score | 69.228 Scores on a scale |
Comparison: Estimate of Difference (least squares mean \[LSM\] difference) = (Sorafenib + Capecitabine) - (Placebo + Capecitabine). The difference between the two treatment groups was evaluated with an analysis of covariance model using the baseline score and the same stratification factors as used for randomization (IVRS) as covariates.95% CI: [-3.619, 0.227]
Other Pre-specified
Patient Reported Outcomes: Functional Assessment of Cancer Therapy-Breast Symptom Index (8 Item) (FBSI-8)
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'.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Capecitabine | Patient Reported Outcomes: Functional Assessment of Cancer Therapy-Breast Symptom Index (8 Item) (FBSI-8) | 20.915 Scores on a scale |
| Placebo + Capecitabine | Patient Reported Outcomes: Functional Assessment of Cancer Therapy-Breast Symptom Index (8 Item) (FBSI-8) | 21.356 Scores on a scale |
Comparison: Estimate of Difference (least squares mean \[LSM\] difference) = (Sorafenib + Capecitabine) - (Placebo + Capecitabine). The difference between the two treatment groups was evaluated with an analysis of covariance model using the baseline score and the same stratification factors as used for randomization (IVRS) as covariates.95% CI: [-0.967, 0.086]