Clinical trial NCT01844674: A Study on the Effect of Vemurafenib on the Pharmacokinetics of a Single Dose of Tizanidine in Patients With BRAFV600 Mutation-Positive Metastatic Malignancies
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malignant Melanoma, Neoplasms
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2013-05-01
Enrollment: 18
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
Primary purpose: OTHER

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).


Eligibility 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

Primary outcomes:
measure: Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Area under the concentration-time curve (AUC)
timeFrame: Pre-dose and up to 12 hours post-dose
measure: Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Maximum plasma concentration (Cmax)
timeFrame: Pre-dose and up to 12 hours post-dose
measure: Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Time to maximum plasma concentration (Tmax)
timeFrame: Pre-dose and up to 12 hours post-dose
measure: Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Terminal half-life (t1/2)
timeFrame: Pre-dose and up to 12 hours post-dose
measure: Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Apparent clearance (CL/F)
timeFrame: Pre-dose and up to 12 hours post-dose
Secondary outcomes:
measure: 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
timeFrame: Up to approximately 9 months
Other outcomes:
Locations:
city: Pleasant Hill
country: United States
facility: Diablo Valley Oncology and Hematology
state: California
city: Detroit
country: United States
facility: Karmanos Cancer Center
state: Michigan
city: Durham
country: United States
facility: Duke University Health Systems
state: North Carolina
city: Rio de Janeiro
country: Brazil
facility: Instituto Nacional do Cancer - INCA
state: RJ
city: Ijui
country: Brazil
facility: Hospital de Caridade de Ijui; Oncologia
state: RS
city: Passo Fundo
country: Brazil
facility: CITO - Centro Integrado de Terapia Onco-Hematológica - Hospital da Cidade de Passo Fundo
state: RS
city: Porto Alegre
country: Brazil
facility: Hospital Sao Lucas - PUCRS
state: RS
city: Greenfield Park
country: Canada
facility: CSSS champlain - Charles-Le Moyne
state: Quebec
city: Nicosia
country: Cyprus
facility: Bank of Cyprus Oncology Center
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center.
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: