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

Phase 1

Completed

• Conditions: Malignant Melanoma, Neoplasms
• Interventions: Drug: Tizanidine; Drug: Vemurafenib

• Registration Number: NCT01844674
• Lead Sponsor: Hoffmann-La Roche

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).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2013-04-29
• Study First Submitted QC: 2013-04-29
• Study First Posted: 2013-05-01
• Study Start: 2013-09-02
• Primary Completion: 2014-08-26
• Study Completion: 2014-08-26
• Status Verified: 2017-03
• Last Update Submitted: 2017-03-16
• Last Update Posted: 2017-03-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 18

Inclusion Criteria

• 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

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Exclusion Criteria

• 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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Pharmacokinetic Population	Vemurafenib	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.
Pharmacokinetic Population	Tizanidine	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (12)

Bank of Cyprus Oncology Center; 🇨🇾 Nicosia, Cyprus

CSSS champlain - Charles-Le Moyne; 🇨🇦 Greenfield Park, Quebec, Canada

Karmanos Cancer Center; 🇺🇸 Detroit, Michigan, United States

Instituto Nacional do Cancer - INCA; 🇧🇷 Rio de Janeiro, RJ, Brazil

Diablo Valley Oncology and Hematology; 🇺🇸 Pleasant Hill, California, United States

Severance Hospital, Yonsei University Health System; 🇰🇷 Seoul, Korea, Republic of

CITO - Centro Integrado de Terapia Onco-Hematológica - Hospital da Cidade de Passo Fundo; 🇧🇷 Passo Fundo, RS, Brazil

Hospital Sao Lucas - PUCRS; 🇧🇷 Porto Alegre, RS, Brazil

Asan Medical Center.; 🇰🇷 Seoul, Korea, Republic of

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

Duke University Health Systems; 🇺🇸 Durham, North Carolina, United States

Hospital de Caridade de Ijui; Oncologia; 🇧🇷 Ijui, RS, Brazil