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]).

Study Overview

• Status: Completed
• Conditions: Malignant Melanoma, Neoplasms
• Intervention / Treatment: Drug: acenocoumarol; Drug: vemurafenib

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Wodonga, New South Wales, Australia, 3690
• Germany
  • Buxtehude, Germany, 21614
  • Essen, Germany, 45122
  • Mannheim, Germany, 68167
• Greece
  • Crete, Greece, 71110
  • Thessaloniki, Greece, 56429
• Hungary
  • Budapest, Hungary, 1122
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
  • Maastricht, Netherlands, 6229HX
  • Utrecht, Netherlands, 3584 CX
• New Zealand
  • Auckland, New Zealand, 1142
  • Christchurch, New Zealand, 8011
• Portugal
  • Lisboa, Portugal, 1099-023
  • Porto, Portugal, 4200-072
• Serbia
  • Belgrade, Serbia, 11000
• Spain
  • Barcelona, Spain, 08036
  • Barcelona, Spain, 08908
  • Madrid, Spain, 28040
  • Madrid, Spain, 28050
  • Madrid, Spain, 28031

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start: August 1, 2013
• Primary Completion (Actual): June 1, 2014
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: May 3, 2013
• First Submitted That Met QC Criteria: May 10, 2013
• First Posted (Estimate): May 13, 2013

Study Record Updates

• Last Update Posted (Estimate): November 2, 2016
• Last Update Submitted That Met QC Criteria: November 1, 2016
• Last Verified: November 1, 2016

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; Anticoagulants; Vemurafenib; Acenocoumarol
• Other Study ID Numbers: GO28397; 2012-003706-27 (EudraCT Number)