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

Study Overview
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Brief Summary
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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]).

Official Title
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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

Conditions
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Malignant Melanoma, Neoplasms

Intervention / Treatment
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* Drug: acenocoumarol
* Drug: vemurafenib


Participation Criteria
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Eligibility Criteria
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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&#8594;A, 1173C&#8594;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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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

Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acenocoumarol + Vemurafenib<br> | Drug: acenocoumarol<br>* 4 mg single oral doses on Days 1 and 23<br>Drug: vemurafenib<br>* 960 mg orally bid, 20 days (Days 4-23)<br>* Other names: Zelboraf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of single-dose acenocoumarol under conditions of vemurafenib steady-state exposure: Area under the concentration-time curve (AUC) |  | Pre-dose and up to 72 hours post-dose | 
| Pharmacokinetics of single-dose acenocoumarol under conditions of vemurafenib steady-state exposure: Maximum plasma concentration (Cmax) |  | Pre-dose and up to 72 hours post-dose | 
| Pharmacokinetics of single-dose acenocoumarol under conditions of vemurafenib steady-state exposure: Time to maximum plasma concentration (Tmax) |  | Pre-dose and up to 72 hours post-dose | 
| Pharmacokinetics of single-dose acenocoumarol under conditions of vemurafenib steady-state exposure: Terminal half-life (t1/2) |  | Pre-dose and up to 72 hours post-dose | 
| Pharmacokinetics of single-dose acenocoumarol under conditions of vemurafenib steady-state exposure: Apparent clearance (CL/F) |  | Pre-dose and up to 72 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Incidence of Adverse Events and Serious Adverse Events |  | approximately 1.5 years |