Malignant Melanoma, Neoplasms
Conditions
Brief summary
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 \[NCT01739764\]).
Interventions
DRUGacenocoumarol
4 mg single oral doses on Days 1 and 23
DRUGvemurafenib
960 mg orally bid, 20 days (Days 4-23)
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| 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
| Measure | Time frame |
|---|---|
| Safety: Incidence of Adverse Events and Serious Adverse Events | approximately 1.5 years |
Countries
Australia, Germany, Greece, Hungary, Netherlands, New Zealand, Portugal, Serbia, Spain
Outcome results
None listed