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

Study Overview
=================
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).

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

Conditions
-----------------
Malignant Melanoma, Neoplasms

Intervention / Treatment
-----------------
* Drug: Tizanidine
* Drug: Vemurafenib


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pharmacokinetic Population<br>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<br>* 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.<br>Drug: Vemurafenib<br>* Participants will receive vemurafenib as multiple oral doses, 960 mg twice daily on Days 2 to 22.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | 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 Outcome Measures

| Outcome Measure | Measure Description | 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 |