A Study on the Effect of Vemurafenib on the Pharmacokinetics of a Single Dose of Tizanidine in Patients With BRAFV600 Mutation-Positive Metastatic Malignancies

NCT01844674 | Completed Phase 1

• 2 other identifiers: GO283962012-003705-94
• Study Type: interventional
• Target: 18
• Locations: 5 countries
• Sites: 12

Brief Summary

This open-label, multicenter, 3-period, fixed-sequence study will evaluate the effect of multiple oral doses of vemurafenib on the pharmacokinetics of a single oral dose of tizanidine in participants with BRAFV600 mutation-positive metastatic malignancies. Participants will receive a single oral dose of tizanidine on Day 1, vemurafenib orally twice daily on Days 2 to 21, and tizanidine and vemurafenib on Day 22. Eligible participants will have the option to continue treatment with vemurafenib as part of an extension study (NCT01739764).

Conditions

Malignant Melanoma, Neoplasms

Outcome Measures

Primary Outcomes (5)

• Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Area under the concentration-time curve (AUC)

  Pre-dose and up to 12 hours post-dose

• Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Maximum plasma concentration (Cmax)

  Pre-dose and up to 12 hours post-dose

• Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Time to maximum plasma concentration (Tmax)

  Pre-dose and up to 12 hours post-dose

• Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Terminal half-life (t1/2)

  Pre-dose and up to 12 hours post-dose

• Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Apparent clearance (CL/F)

  Pre-dose and up to 12 hours post-dose

Secondary Outcomes (1)

• Safety: Incidence, nature and severity of adverse events and serious adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0

  Up to approximately 9 months

Study Arms (1)

Pharmacokinetic Population

EXPERIMENTAL

All participants will receive a 3-period treatment including single-dose tizanidine on Day 1, twice-daily vemurafenib on Days 2 to 21, and both agents together on Day 22.

Drug: Tizanidine; Drug: Vemurafenib

Interventions

Tizanidine DRUG

Participants will receive tizanidine as single oral doses, 2 milligrams (mg) on Day 1 and repeated on Day 22, each following an overnight fast \>/= 10 hours.

Pharmacokinetic Population

Vemurafenib DRUG

Participants will receive vemurafenib as multiple oral doses, 960 mg twice daily on Days 2 to 22.

Pharmacokinetic Population

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults 18 to 70 years of age, inclusive
• Unresectable Stage IIIc or IV metastatic melanoma positive for the BRAFV600 mutation or other malignant tumor type which harbors a V600 activating mutation of BRAF, as determined by Cobas 4800 BRAFV600 Mutation Test or a DNA sequencing method
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
• Life expectancy greater than or equal to (\>/=) 12 weeks
• Participant has not consumed tobacco or nicotine-containing products for 42 days prior to first dose of study drug, and must agree to refrain from such products while on study
• Adequate hematologic, renal and liver function

You may not qualify if:

• Prior treatment with vemurafenib or other BRAF inhibitor within 42 days of Day 1
• History of or current clinically significant cardiac or pulmonary dysfunction, including current uncontrolled Grade \>/= 2 hypertension or unstable angina
• Current dyspnea at rest due to complications of advanced malignancy or any requirement for supplemental oxygen
• Active central nervous system lesions (participants with radiographically unstable, symptomatic lesions)
• Participants with CYP1A2 gene mutation (-3113G-\>A), either in one or two alleles
• Allergy or hypersensitivity to vemurafenib or tizanidine formulations
• Current severe uncontrolled systemic disease
• Inability or unwillingness to swallow pills
• History of malabsorption or other condition that would interfere with enteral absorption of study treatment
• History of clinically significant liver disease (including cirrhosis), current alcohol abuse, or human immunodeficiency (HIV) infection requiring antiretroviral treatment, acquired immune deficiency syndrome (AIDS)-related illness, or active hepatitis B or C
• Pregnant or breastfeeding women

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (12)

Diablo Valley Oncology and Hematology

Pleasant Hill, California, 94523, United States

Location

Karmanos Cancer Center

Detroit, Michigan, 48201, United States

Location

Duke University Health Systems

Durham, North Carolina, 27710, United States

Location

Instituto Nacional do Cancer - INCA

Rio de Janeiro, Rio de Janeiro, 20560-120, Brazil

Location

Hospital de Caridade de Ijui; Oncologia

Ijuí, Rio Grande do Sul, 98700-000, Brazil

Location

CITO - Centro Integrado de Terapia Onco-Hematológica - Hospital da Cidade de Passo Fundo

Passo Fundo, Rio Grande do Sul, 99010-260, Brazil

Location

Hospital Sao Lucas - PUCRS

Porto Alegre, Rio Grande do Sul, 90610-000, Brazil

Location

CSSS champlain - Charles-Le Moyne

Greenfield Park, Quebec, J4V 2H1, Canada

Location

Bank of Cyprus Oncology Center

Nicosia, 2006, Cyprus

Location

Severance Hospital, Yonsei University Health System

Seoul, 03722, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

Asan Medical Center.

Seoul, 138-736, South Korea

Location

MeSH Terms

Conditions

Melanoma; Neoplasms

Interventions

tizanidine; Vemurafenib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 29, 2013
• First Posted: May 1, 2013
• Study Start: September 2, 2013
• Primary Completion: August 26, 2014
• Study Completion: August 26, 2014
• Last Updated: March 20, 2017

Record last verified: 2017-03

Locations

BR (4); KR (3); US (3); CY (1); CA (1)