A Study of the Effect of Vemurafenib on the Pharmacokinetics of Acenocoumarol in Patients With BRAFV600 Mutation-Positive Metastatic Malignancy

A PHASE I, OPEN-LABEL, MULTICENTER, 3-PERIOD, FIXED-SEQUENCE STUDY TO INVESTIGATE THE EFFECT OF VEMURAFENIB ON THE PHARMACOKINETICS OF A SINGLE ORAL DOSE OF ACENOCOUMAROL IN PATIENTS WITH BRAFV600 MUTATION-POSITIVE METASTATIC MALIGNANCY

This open-label, multicenter, 3-period, fixed-sequence study will evaluate the effect of multiple doses of vemurafenib on the pharmacokinetics of a single dose of acenocoumarol in participants with BRAFV600 mutation-positive metastatic malignancies. Participants will receive a single dose of acenocoumarol 4 mg orally on Day 1 and Day 23, vemurafenib 960 mg orally twice daily on Days 4-26. After completion of pharmacokinetic assessments on Day 26, eligible participants will have the option to continue treatment with vemurafenib as part of an extension study (GO28399 [NCT01739764]).

Inclusion Criteria:

• Adult patients, 18-70 years of age
• Patients with either unresectable Stage IIIc or IV BRAFV600 mutation-positive metastatic melanoma or other malignant BRAFV600 mutation-positive tumor type and who have no acceptable standard treatment options
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
• Full recovery from any major surgery or significant traumatic injury at least 14 days prior to the first dose of study treatment
• Adequate hematologic and end organ function
• Female patients of childbearing potential and male patients with female partners of childbearing potential must agree to use 2 effective methods of contraception as defined by protocol during the course of the study and for at least 6 months after completion of study treatment

Exclusion Criteria:

• Prior treatment with vemurafenib or other BRAF inhibitor within 42 days of Day 1
• Prior anti-cancer therapy within 28 days (6 weeks for nitrosureas or mitocyn C, or 14 days for hormonal therapy or kinase inhibitors) before the first dose of study treatment Day 1
• Palliative radiotherapy within 2 weeks prior to first dose of study treatment Day 1
• Experimental therapy within 4 weeks prior to first dose of study treatment Day 1
• History of clinically significant cardiac or pulmonary dysfunction, including current uncontrolled Grade >/=2 hypertension or unstable angina
• Current Grade >/=2 dyspnea or hypoxia or need for oxygen supplementation
• History of myocardial infarction within 6 months prior to first dose of study treatment
• Active central nervous system lesions (i.e. participants with radiographically unstable, symptomatic lesions)
• History of bleeding or coagulation disorders
• Allergy or hypersensitivity to vemurafenib or acenocoumarol formulations
• History of malabsorption or other condition that would interfere with the enteral absorption of study treatment
• Participants with VKORC1 mutations (1639G→A, 1173C→T) in either one allele (heterozygous)or two alleles (homozygous)
• Participants with CYP2C9*3 mutations in either one allele (heterozygous) or two alleles (homozygous)
• History of clinically significant liver disease (including cirrhosis), current alcohol abuse, or active hepatitis B or hepatitis C virus infection
• Human immunodeficiency virus (HIV) infection requiring antiretroviral treatment, or AIDS-related illness
• Pregnant or lactating women