Clinical trial NCT01851824: A Study of the Effect of Vemurafenib on the Pharmacokinetics of Acenocoumarol in Patients With BRAFV600 Mutation-Positive Metastatic Malignancy
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malignant Melanoma, Neoplasms
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2013-05-13
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP

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 \[NCT01739764\]).


Eligibility criteria: 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

Primary outcomes:
measure: Pharmacokinetics of single-dose acenocoumarol under conditions of vemurafenib steady-state exposure: Area under the concentration-time curve (AUC)
timeFrame: Pre-dose and up to 72 hours post-dose
measure: Pharmacokinetics of single-dose acenocoumarol under conditions of vemurafenib steady-state exposure: Maximum plasma concentration (Cmax)
timeFrame: Pre-dose and up to 72 hours post-dose
measure: Pharmacokinetics of single-dose acenocoumarol under conditions of vemurafenib steady-state exposure: Time to maximum plasma concentration (Tmax)
timeFrame: Pre-dose and up to 72 hours post-dose
measure: Pharmacokinetics of single-dose acenocoumarol under conditions of vemurafenib steady-state exposure: Terminal half-life (t1/2)
timeFrame: Pre-dose and up to 72 hours post-dose
measure: Pharmacokinetics of single-dose acenocoumarol under conditions of vemurafenib steady-state exposure: Apparent clearance (CL/F)
timeFrame: Pre-dose and up to 72 hours post-dose
Secondary outcomes:
measure: Safety: Incidence of Adverse Events and Serious Adverse Events
timeFrame: approximately 1.5 years
Other outcomes:
Locations:
city: Wodonga
country: Australia
state: New South Wales
city: Buxtehude
country: Germany
city: Essen
country: Germany
city: Mannheim
country: Germany
city: Crete
country: Greece
city: Thessaloniki
country: Greece
city: Budapest
country: Hungary
city: Amsterdam
country: Netherlands
city: Maastricht
country: Netherlands
city: Utrecht
country: Netherlands
city: Auckland
country: New Zealand
city: Christchurch
country: New Zealand
city: Lisboa
country: Portugal
city: Porto
country: Portugal
city: Belgrade
country: Serbia
city: Barcelona
country: Spain
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: