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

Malignant Melanoma, Neoplasms Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01844674
• Other study ID #: GO28396
• Secondary ID: 2012-003705-94
• Status: Completed
• Phase: Phase 1
• First received: April 29, 2013
• Last updated: March 16, 2017
• Start date: September 2, 2013
• Est. completion date: August 26, 2014

Study information

• Verified date: March 2017
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 18
• Est. completion date: August 26, 2014
• Est. primary completion date: August 26, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Malignant Melanoma, Neoplasms
• Melanoma

Intervention

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.
• Vemurafenib
Participants will receive vemurafenib as multiple oral doses, 960 mg twice daily on Days 2 to 22.

Locations

Country	Name	City	State
Brazil	Hospital de Caridade de Ijui; Oncologia	Ijui	RS
Brazil	CITO - Centro Integrado de Terapia Onco-Hematológica - Hospital da Cidade de Passo Fundo	Passo Fundo	RS
Brazil	Hospital Sao Lucas - PUCRS	Porto Alegre	RS
Brazil	Instituto Nacional do Cancer - INCA	Rio de Janeiro	RJ
Canada	CSSS champlain - Charles-Le Moyne	Greenfield Park	Quebec
Cyprus	Bank of Cyprus Oncology Center	Nicosia
Korea, Republic of	Asan Medical Center.	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
United States	Karmanos Cancer Center	Detroit	Michigan
United States	Duke University Health Systems	Durham	North Carolina
United States	Diablo Valley Oncology and Hematology	Pleasant Hill	California

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  Cyprus,  Korea, Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Maximum plasma concentration (Cmax)		Pre-dose and up to 12 hours post-dose
Primary	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
Primary	Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Terminal half-life (t1/2)		Pre-dose and up to 12 hours post-dose
Primary	Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Apparent clearance (CL/F)		Pre-dose and up to 12 hours post-dose
Secondary	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