Study design
This open-label, multicenter, phase I study enrolled two cohorts: a pharmacokinetic cohort and an expansion cohort. For the pharmacokinetic cohort, patients received treatment in three periods after a 28-day screening period. In period A (days 1–21), patients received oral vemurafenib 960 mg twice daily. Patients fasted overnight for at least 8 h before and at least 4 h after the morning dose on days 1 and 21. Light snacks (crackers, toast, water, and juice) were allowed in the 4-h post-dose period. All other doses were administered either 1 h before or 2 h after a meal. Only the morning dose was administered on day 21. In period B (days 22–27), patients temporarily discontinued vemurafenib to enable characterization of the elimination profile. In period C (day 28 onwards), patients continued to receive vemurafenib 960 mg twice daily until disease progression, unacceptable toxicity, withdrawal of consent, or discontinuation for any other reason.
Enrollment in the expansion cohort was initiated after completion of recruitment into the pharmacokinetic cohort. In the expansion cohort, all patients received vemurafenib 960 mg twice daily until progressive disease, unacceptable toxicity, withdrawal of consent, or discontinuation for any other reason. Dose modifications (temporary interruption or dose reductions) were allowed within both cohorts for management of symptomatic adverse events (AEs).
This study was conducted in accordance with International Congress on Harmonisation guidelines for Good Clinical Practice, the principles of the Declaration of Helsinki, and local regulations. All patients provided written informed consent. This trial was registered prospectively at ClinicalTrials.gov (ID, NCT01910181) on July 29, 2013. The trial was designed jointly by the corresponding author and the sponsor (F. Hoffmann-La Roche Ltd). Data were collected by the site investigators and were retained and analyzed by the sponsor. All authors had full access to the data.
Patients
Chinese patients ≥18 years of age with histologically confirmed metastatic melanoma (unresectable stage IIIC or stage IV) positive for BRAFV600 mutation by cobas® BRAF V600 Mutation Test (Roche Molecular Diagnostics, Pleasanton, CA, USA) were eligible. Other key inclusion criteria included measurable disease according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1); Eastern Cooperative Oncology Group performance status 0–1; adequate hematologic, renal, and liver function; life expectancy > 3 months; and absence of active central nervous system metastases. Patients could be treatment-naive or have previously received systemic therapy (excluding BRAF or MEK inhibitors).
Outcomes and assessments
The primary objective was to evaluate the pharmacokinetics of vemurafenib 960 mg twice daily in Chinese patients, including maximal concentration (Cmax); time to maximal concentration (tmax); area under the concentration-time curve from 0 to 8 hours (AUC0-8h), AUC0-12h, and AUC0-168h; trough concentration (Ctrough); accumulation ratio (defined as AUC0-8h on day 21/AUC0-8h on day 1); terminal elimination rate constant (Kel); and terminal half-life (t½). The schedule of assessments is in the Additional file 1. Pharmacokinetic parameters were calculated using noncompartmental analysis (Phoenix WinNonlin, version 6.2; Pharsight, a Certara company, Princeton, NJ, USA).
Efficacy endpoints included best overall response rate (BORR) according to RECIST v1.1, confirmed by repeat assessment at least 4 weeks after criteria were first met, PFS, OS, and duration of response (DOR). Tumor assessments (computed tomography or magnetic resonance imaging) were obtained at screening, day 1 of cycle 3, and every 2 cycles thereafter (or as clinically indicated) until documented disease progression. DOR, PFS, and OS were estimated using the Kaplan-Meier method.
Safety assessments consisted of monitoring and recording of AEs, serious AEs, and nonserious AEs of special interest; protocol-specified laboratory assessments; vital signs; and other protocol-specified tests. AEs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Patients were followed for safety for 28 days after the last dose of study medication or until resolution of drug-related AEs. All patients who received at least one dose of vemurafenib were to be followed for evaluation of cutaneous squamous cell carcinoma (cuSCC) until 6 months after discontinuation of study treatment, or until death, withdrawal of consent, or loss to follow-up, whichever occurred first.
The pharmacokinetic analysis population included all patients who provided sufficient pharmacokinetic data to obtain at least one of the primary pharmacokinetic variables. The safety population included all patients who received at least one dose of vemurafenib, and the tumour response population included all patients.
Statistical analysis
No formal sample size calculation was performed. The sample size of 20 patients in the pharmacokinetic cohort was chosen to characterize the vemurafenib pharmacokinetic profile with consideration of interpatient variability. With 20 patients enrolled in the pharmacokinetic cohort, at least 10 patients would be expected to complete the pharmacokinetic portion of the study. A total of 45 patients (20 in the pharmacokinetic cohort and 25 in the expansion cohort) would give a Clopper-Pearson 95% CI of 26–56% for BORR, assuming the target BORR (confirmed) is 40%.