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

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

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.

Study Overview

• Status: Completed
• Conditions: Malignant Melanoma
• Intervention / Treatment: Drug: Vemurafenib

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100142
    • Beijing Cancer Hospital
  • Guangzhou, China, 510060
    • Sun Yet-sen University Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vemurafenib: Pharmacokinetic Cohort; 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; Participants will receive vemurafenib at a dose of 960 mg twice daily orally.; Other Names: Zelboraf
Experimental: Vemurafenib: Expansion Cohort; 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; Participants will receive vemurafenib at a dose of 960 mg twice daily orally.; Other Names: Zelboraf

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Si L, Zhang X, Xu Z, Jiang Q, Bu L, Wang X, Mao L, Zhang W, Richie N, Guo J. Vemurafenib in Chinese patients with BRAFV600 mutation-positive unresectable or metastatic melanoma: an open-label, multicenter phase I study. BMC Cancer. 2018 May 3;18(1):520. doi: 10.1186/s12885-018-4336-3.

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2013
• Primary Completion (Actual): October 22, 2013
• Study Completion (Actual): April 20, 2018

Study Registration Dates

• First Submitted: July 25, 2013
• First Submitted That Met QC Criteria: July 25, 2013
• First Posted (Estimate): July 29, 2013

Study Record Updates

• Last Update Posted (Actual): May 29, 2019
• Last Update Submitted That Met QC Criteria: May 26, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Vemurafenib
• Other Study ID Numbers: YO28390