Malignant Melanoma, Neoplasms
Conditions
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).
Interventions
DRUGTizanidine
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.
DRUGVemurafenib
Participants will receive vemurafenib as multiple oral doses, 960 mg twice daily on Days 2 to 22.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| 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 | Up to approximately 9 months |
Countries
Brazil, Canada, Cyprus, South Korea, United States
Outcome results
None listed