A Study of Vemurafenib (Zelboraf) in Chinese Participants With BRAF V600 Mutation-Positive Unresectable or Metastatic Melanoma

Study Overview
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Brief Summary
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This open-label, multicenter study will evaluate the pharmacokinetics, safety and efficacy of vemurafenib in Chinese participants with BRAF V600 mutation-positive unresectable or metastatic melanoma. Participants will receive vemurafenib 960 milligrams (mg) orally twice daily until disease progression or unacceptable toxicity occurs.

Official Title
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A Phase I Open-Label, Multicenter, Multiple-Dose Study to Investigate the Pharmacokinetics, Safety, and Efficacy of Vemurafenib in Chinese Patients With BRAF V600 Mutation-Positive Unresectable or Metastatic Melanoma

Conditions
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Malignant Melanoma

Intervention / Treatment
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* Drug: Vemurafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chinese male or female participants, greater than or equal to (≥) 18 years of age Histologically confirmed metastatic melanoma (surgically unresectable Stage IIIC or Stage IV, American Joint Committee on Cancer) Treatment-naïve or having received prior systemic treatments for metastatic melanoma Positive BRAF V600 mutation result determined by a designated laboratory using the Cobas 4800 BRAF V600 Mutation Test Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Previous allowed chemotherapy, immunotherapy, or radiation therapy must have been completed at least 2 weeks prior to study drug administration, and all associated toxicity must be resolved (to less than or equal to [≤] Grade 1 or baseline) Recovery from effects of any major surgery (excluding tumor biopsy at baseline) or significant traumatic injury at least 14 days before the first dose of study treatment Adequate hematologic, renal, and liver function as defined by protocol Fertile men and women must use an effective method of contraception during treatment and for ≥6 months after completion of treatment as directed by their physician (in accordance with local requirements). Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Life expectancy greater than (>) 3 months Able to swallow pills Exclusion Criteria: Active central nervous system (CNS) lesions (radiographically unstable/symptomatic lesions), except participants treated with stereotactic therapy or surgery who remain without evidence of disease progression in brain for ≥3 months and have been off corticosteroid and anticonvulsant therapy for ≥3 weeks History of or known spinal cord compression or carcinomatous meningitis Anticipated or ongoing administration of anti-cancer therapies other than those administered in this study Active squamous cell carcinoma (SCC) that has not been excised or has not yet adequately healed post excision Pregnant or lactating women Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant small bowel resection that would preclude adequate vemurafenib absorption Any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, serious cardiac arrhythmia requiring medication, uncontrolled hypertension, cerebrovascular accident or transient ischemic attack, or symptomatic pulmonary embolism Known clinically significant active infection History of allogeneic bone marrow transplantation or organ transplantation Previous malignancy within the past 5 years other than adequately treated basal cell carcinoma or SCC of the skin, melanoma in-situ, and carcinoma in-situ of the cervix and/or curatively treated cancer from which the participant is currently disease-free, or any malignancy from which the participant has been continuously disease-free for at least 5 years Previous treatment with a BRAF inhibitor (sorafenib allowed) or MEK inhibitor Participants who have had one or more doses of vemurafenib in a previous clinical trial Known human immunodeficiency virus (HIV) positivity or acquired immune deficiency syndrome (AIDS)-related illness, or hepatitis B virus or hepatitis C virus (HCV) carriers (hepatitis B surface antigen-positive, HCV antibody-positive) Received any investigational treatment within 4 weeks of study drug start

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vemurafenib: Pharmacokinetic Cohort<br>Participants will receive vemurafenib orally as 960 mg twice daily on Days 1 to 21 (morning dose only on Day 21), with a drug holiday from Days 22 to 27, and from Day 28 until progression, unacceptable toxicity, consent withdrawal, decision by the investigator or Sponsor, or protocol/eligibility violation. | Drug: Vemurafenib<br>* Participants will receive vemurafenib at a dose of 960 mg twice daily orally.<br>* Other names: Zelboraf;|
| Experimental: Vemurafenib: Expansion Cohort<br>Participants will receive vemurafenib orally as 960 mg twice daily from Day 1 until progression, unacceptable toxicity, consent withdrawal, decision by the investigator or Sponsor, or protocol/eligibility violation. | Drug: Vemurafenib<br>* Participants will receive vemurafenib at a dose of 960 mg twice daily orally.<br>* Other names: Zelboraf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 From 0 to 8 Hours on Day 1 | Plasma PK samples were obtained from each participant for calculation of AUC from 0 to 8 hours, using the linear trapezoid rule. The value was averaged among all participants and expressed in hours by micrograms per milliliter (h*μg/mL). | Pre-dose (0 hours) and post-dose (1, 2, 4, 5, 8 hours) on Day 1 | 
| AUC of RO5185426 From 0 to 8 Hours on Day 21 | Plasma PK samples were obtained from each participant for calculation of AUC from 0 to 8 hours, using the linear trapezoid rule. The value was averaged among all participants and expressed in h*μg/mL. | Pre-dose (0 hours) and post-dose (1, 2, 4, 5, 8 hours) on Day 21 | 
| AUC of RO5185426 From 0 to 12 Hours on Day 1 | Plasma PK samples were obtained from each participant for calculation of AUC from 0 to 12 hours, using the linear trapezoid rule. The value was averaged among all participants and expressed in h*μg/mL. | Pre-dose (0 hours) and post-dose (1, 2, 4, 5, 8, 12 hours) on Day 1 | 
| AUC of RO5185426 From 0 to 12 Hours on Day 21 | Plasma PK samples were obtained from each participant for calculation of AUC from 0 to 12 hours, using the linear trapezoid rule. The value was averaged among all participants and expressed in h*μg/mL. | Pre-dose (0 hours) and post-dose (1, 2, 4, 5, 8, 12 hours) on Day 21 | 
| Maximum Plasma Concentration (Cmax) of RO5185426 on Day 1 | Plasma PK samples were obtained from each participant, and the maximum observed post-dose concentration was recorded. The value was averaged among all participants and expressed in micrograms per milliliter (μg/mL). | Pre-dose (0 hours) and post-dose (1, 2, 4, 5, 8, 12 hours) on Day 1 | 
| Cmax of RO5185426 Following Day 21 Dose | Plasma PK samples were obtained from each participant, and the maximum observed post-dose concentration was recorded. The value was averaged among all participants and expressed in μg/mL. | Pre-dose (0 hours) and post-dose (1, 2, 4, 5, 8, 12, 24, 28, 72, 76, 168 hours) from Day 21 | 
| Time of Maximum Plasma Concentration (Tmax) of RO5185426 on Day 1 | Plasma PK samples were obtained from each participant, and the time of maximum post-dose concentration was recorded. The median value was derived from all participants and expressed in hours. | Pre-dose (0 hours) and post-dose (1, 2, 4, 5, 8, 12 hours) on Day 1 | 
| Tmax of RO5185426 Following Day 21 Dose | Plasma PK samples were obtained from each participant, and the time of maximum post-dose concentration was recorded. The median value was derived from all participants and expressed in hours. | Pre-dose (0 hours) and post-dose (1, 2, 4, 5, 8, 12, 24, 28, 72, 76, 168 hours) from Day 21 | 
| AUC From 0 to 168 Hours of RO5185426 Following Day 21 Dose | Plasma PK samples were obtained from each participant for calculation of AUC from 0 to 168 hours, using the linear trapezoid rule. The value was averaged among all participants and expressed in h*μg/mL. | Pre-dose (0 hours) and post-dose (1, 2, 4, 5, 8, 12, 24, 28, 72, 76, 168 hours) from Day 21 | 
| Elimination Half-Life (t1/2) of RO5185426 Following Day 21 Dose | Plasma PK samples were obtained from each participant for calculation of t1/2, defined as the time elapsed for plasma concentrations to drop by half. The value was averaged among all participants and expressed in hours. | Pre-dose (0 hours) and post-dose (1, 2, 4, 5, 8, 12, 24, 28, 72, 76, 168 hours) from Day 21 | 
| Trough Plasma Concentration (Ctrough) of RO5185426 on Day 15 | Plasma PK samples were obtained from each participant, and the concentration immediately prior to drug administration was recorded. The value was averaged among all participants and expressed in μg/mL. | Pre-dose (0 hours) on Day 15 | 
| Ctrough of RO5185426 on Day 19 | Plasma PK samples were obtained from each participant, and the concentration immediately prior to drug administration was recorded. The value was averaged among all participants and expressed in μg/mL. | Pre-dose (0 hours) on Day 19 | 
| Ctrough of RO5185426 on Day 21 | Plasma PK samples were obtained from each participant, and the concentration immediately prior to drug administration was recorded. The value was averaged among all participants and expressed in μg/mL. | Pre-dose (0 hours) on Day 21 | 
| Accumulation Ratio of RO5185426 AUC From 0 to 8 Hours Between Day 21 and Day 1 | Plasma PK samples were obtained from each participant for calculation of AUC from 0 to 8 hours, using the linear trapezoid rule. The AUC on Day 21 was divided by the AUC for Day 1. The resulting value was averaged among all participants and expressed as the accumulation ratio. | Pre-dose (0 hours) and post-dose (1, 2, 4, 5, 8 hours) on Days 1 and 21 | 
| Terminal Elimination Rate Constant (Kel) of RO5185426 on Day 21 | Plasma PK samples were obtained from each participant and the kel was estimated. The value was averaged among all participants and expressed in inverse hours (h^-1). | Pre-dose (0 hours) and post-dose (1, 2, 4, 5, 8, 12, 24, 28, 72, 76, 168 hours) from Day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | Tumor response was evaluated using RECIST version 1.1 criteria. CR was defined as disappearance of all target lesions and short-axis reduction of any pathological lymph nodes to less than (<) 10 millimeters (mm). PR was defined as greater than or equal to (≥) 30 percent (%) decrease from Baseline in sum diameter of target lesions. The percentage of participants with a best overall response of CR or PR during the study was reported. | Tumor assessments at Screening, Day 1 of Cycle 3, and every two cycles (cycle length of 28 days) thereafter until disease progression (up to 16 months as of data cutoff 15-Dec-2014) | 
| Percentage of Participants With Disease Progression or Death Among Participants With a Previous Assessment of CR or PR According to RECIST Version 1.1 | Tumor response was evaluated using RECIST version 1.1 criteria. CR was defined as disappearance of all target lesions and short-axis reduction of any pathological lymph nodes to <10 mm. PR was defined as ≥30) decrease from Baseline in sum diameter of target lesions. Disease progression was defined as ≥20% increase on-study in sum diameter of target lesions with absolute increase ≥5 mm, or the appearance of new lesion(s). The percentage of participants who died or progressed after CR or PR was reported. | Tumor assessments at Screening, Day 1 of Cycle 3, and every two cycles (cycle length of 28 days) thereafter until disease progression; survival followed every 3 months until discontinuation from study (up to 16 months as of data cutoff 15-Dec-2014) | 
| Duration of Response According to RECIST Version 1.1 | Tumor response was evaluated using RECIST version 1.1 criteria. CR was defined as disappearance of all target lesions and short-axis reduction of any pathological lymph nodes to <10 mm. PR was defined as ≥30) decrease from Baseline in sum diameter of target lesions. Disease progression was defined as ≥20% increase on-study in sum diameter of target lesions with absolute increase ≥5 mm, or the appearance of new lesion(s). Duration of response was defined as the time from initial response of CR or PR to the first event of disease progression or death. Median time to event was estimated using Kaplan-Meier analysis, and the 95% confidence interval (CI) was estimated using the Brookmeyer-Crowley method. | Tumor assessments at Screening, Day 1 of Cycle 3, and every two cycles (cycle length of 28 days) thereafter until disease progression; survival followed every 3 months until discontinuation from study (up to 16 months as of data cutoff 15-Dec-2014) | 
| Percentage of Participants With Death or Disease Progression According to RECIST Version 1.1 | Tumor response was evaluated using RECIST version 1.1 criteria. Disease progression was defined as ≥20% increase on-study in sum diameter of target lesions with absolute increase ≥5 mm, or the appearance of new lesion(s). The percentage of participants with death or disease progression during the study was reported. | Tumor assessments at Screening, Day 1 of Cycle 3, and every two cycles (cycle length of 28 days) thereafter until disease progression; survival followed every 3 months until discontinuation from study (up to 16 months as of data cutoff 15-Dec-2014) | 
| Progression-Free Survival (PFS) | Tumor response was evaluated using RECIST version 1.1 criteria. Disease progression was defined as ≥20% increase on-study in sum diameter of target lesions with absolute increase ≥5 mm, or the appearance of new lesion(s). PFS was defined as the time from treatment start to the first event of disease progression or death. Median time to event was estimated using Kaplan-Meier analysis, and the 95% CI was estimated using the Brookmeyer-Crowley method. | Tumor assessments at Screening, Day 1 of Cycle 3, and every two cycles (cycle length of 28 days) thereafter until disease progression; survival followed every 3 months until discontinuation from study (up to 16 months as of data cutoff 15-Dec-2014) | 
| Percentage of Participants Who Died | The percentage of participants who died during the study was reported. | Throughout treatment (up to 16 months); survival followed every 3 months until discontinuation from study | 
| Overall Survival (OS) | OS was defined as the time from treatment start to death from any cause. Median time to event was estimated using Kaplan-Meier analysis, and the 95% CI was estimated using the Brookmeyer-Crowley method. | Throughout treatment (up to 16 months); survival followed every 3 months until discontinuation from study |