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

March 16, 2017 updated by: Hoffmann-La Roche

A Phase I, Open-Label, Multicenter, 3- Period, Fixed-Sequence Study to Investigate the Effect of Vemurafenib on the Pharmacokinetics of a Single Dose of Tizanidine (a CYP1A2 Substrate) in Patients With BRAFV600 Mutation-Positive Metastatic Malignancy

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).

Study Overview

Status

Completed

Study Type

Interventional

Enrollment (Actual)

18

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • RJ
      • Rio de Janeiro, RJ, Brazil, 20560-120
        • Instituto Nacional do Cancer - INCA
    • RS
      • Ijui, RS, Brazil, 98700-000
        • Hospital de Caridade de Ijui; Oncologia
      • Passo Fundo, RS, Brazil, 99010-260
        • CITO - Centro Integrado de Terapia Onco-Hematológica - Hospital da Cidade de Passo Fundo
      • Porto Alegre, RS, Brazil, 90610-000
        • Hospital Sao Lucas - PUCRS
    • Quebec
      • Greenfield Park, Quebec, Canada, J4V 2H1
        • CSSS champlain - Charles-Le Moyne
      • Nicosia, Cyprus, 2006
        • Bank of Cyprus Oncology Center
      • Seoul, Korea, Republic of, 03722
        • Severance Hospital, Yonsei University Health System
      • Seoul, Korea, Republic of, 06351
        • Samsung Medical Center
      • Seoul, Korea, Republic of, 138-736
        • Asan Medical Center.
    • California
      • Pleasant Hill, California, United States, 94523
        • Diablo Valley Oncology and Hematology
    • Michigan
      • Detroit, Michigan, United States, 48201
        • Karmanos Cancer Center
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke University Health Systems

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 68 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Pharmacokinetic Population
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.
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.
Participants will receive vemurafenib as multiple oral doses, 960 mg twice daily on Days 2 to 22.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Area under the concentration-time curve (AUC)
Time Frame: Pre-dose and up to 12 hours post-dose
Pre-dose and up to 12 hours post-dose
Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Maximum plasma concentration (Cmax)
Time Frame: Pre-dose and up to 12 hours post-dose
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)
Time Frame: Pre-dose and up to 12 hours post-dose
Pre-dose and up to 12 hours post-dose
Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Terminal half-life (t1/2)
Time Frame: Pre-dose and up to 12 hours post-dose
Pre-dose and up to 12 hours post-dose
Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Apparent clearance (CL/F)
Time Frame: Pre-dose and up to 12 hours post-dose
Pre-dose and up to 12 hours post-dose

Secondary Outcome Measures

Outcome Measure
Time Frame
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
Time Frame: Up to approximately 9 months
Up to approximately 9 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 2, 2013

Primary Completion (Actual)

August 26, 2014

Study Completion (Actual)

August 26, 2014

Study Registration Dates

First Submitted

April 29, 2013

First Submitted That Met QC Criteria

April 29, 2013

First Posted (Estimate)

May 1, 2013

Study Record Updates

Last Update Posted (Actual)

March 20, 2017

Last Update Submitted That Met QC Criteria

March 16, 2017

Last Verified

March 1, 2017

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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