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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01844674
First received: April 29, 2013
Last updated: April 2, 2016
Last verified: April 2016
  Purpose
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).

Condition Intervention Phase
Malignant Melanoma, Neoplasms
Drug: Tizanidine
Drug: Vemurafenib
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study
Masking: Open Label
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 Dose of Tizanidine (a CYP1A2 Substrate) in Patients With BRAFV600 Mutation-Positive Metastatic Malignancy

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]

Enrollment: 18
Study Start Date: September 2013
Study Completion Date: August 2014
Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Tizanidine
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.
Drug: Vemurafenib
Participants will receive vemurafenib as multiple oral doses, 960 mg twice daily on Days 2 to 22.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01844674

Locations
United States, California
Pleasant Hill, California, United States, 94523
United States, Michigan
Detroit, Michigan, United States, 48201
United States, North Carolina
Durham, North Carolina, United States, 27710
Brazil
Rio de Janeiro, RJ, Brazil, 20560-120
Ijui, RS, Brazil, 98700-000
Passo Fundo, RS, Brazil, 99010-260
Porto Alegre, RS, Brazil, 90610-000
Canada, Quebec
Greenfield Park, Quebec, Canada, J4V 2H1
Cyprus
Nicosia, Cyprus, 2006
Korea, Republic of
Seoul, Korea, Republic of, 03722
Seoul, Korea, Republic of, 06351
Seoul, Korea, Republic of, 138-736
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01844674     History of Changes
Other Study ID Numbers: GO28396  2012-003705-94 
Study First Received: April 29, 2013
Last Updated: April 2, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Tizanidine
Clonidine
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anticonvulsants
Muscle Relaxants, Central
Neuromuscular Agents
Parasympatholytics
Autonomic Agents
Adrenergic alpha-2 Receptor Agonists
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Sympatholytics

ClinicalTrials.gov processed this record on July 28, 2016