Trial Review

Registering a new trial?

To achieve prospective registration, we recommend submitting your trial for registration at the same time as ethics submission.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01844674




Registration number
NCT01844674
Ethics application status
Date submitted
29/04/2013
Date registered
1/05/2013
Date last updated
20/03/2017

Titles & IDs
Public title
A Study on the Effect of Vemurafenib on the Pharmacokinetics of a Single Dose of Tizanidine in Patients With BRAFV600 Mutation-Positive Metastatic Malignancies
Scientific 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
Secondary ID [1] 0 0
2012-003705-94
Secondary ID [2] 0 0
GO28396
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malignant Melanoma, Neoplasms 0 0
Hepatitis C 0 0
Condition category
Condition code
Cancer 0 0 0 0
Malignant melanoma
Infection 0 0 0 0
Other infectious diseases
Oral and Gastrointestinal 0 0 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Tizanidine
Treatment: Drugs - Vemurafenib

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.

Experimental: VX-135 High Dose with Daclatasvir - 12 weeks of a high dose of VX-135 in combination with Daclatasvir

Experimental: VX-135 Low Dose with Daclatasvir - 12 weeks of a low dose of VX-135 in combination with Daclatasvir


Treatment: Drugs: 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.

Treatment: Drugs: Vemurafenib
Participants will receive vemurafenib as multiple oral doses, 960 mg twice daily on Days 2 to 22.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Area under the concentration-time curve (AUC)
Timepoint [1] 0 0
Pre-dose and up to 12 hours post-dose
Primary outcome [2] 0 0
Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Maximum plasma concentration (Cmax)
Timepoint [2] 0 0
Pre-dose and up to 12 hours post-dose
Primary outcome [3] 0 0
Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Time to maximum plasma concentration (Tmax)
Timepoint [3] 0 0
Pre-dose and up to 12 hours post-dose
Primary outcome [4] 0 0
Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Terminal half-life (t1/2)
Timepoint [4] 0 0
Pre-dose and up to 12 hours post-dose
Primary outcome [5] 0 0
Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Apparent clearance (CL/F)
Timepoint [5] 0 0
Pre-dose and up to 12 hours post-dose
Primary outcome [6] 0 0
The safety and tolerability as assessed by adverse events (AEs), vital signs, 12-lead electrocardiograms (ECGs), echocardiograms, and laboratory assessments
Timepoint [6] 0 0
Up to 64 weeks
Secondary outcome [1] 0 0
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
Timepoint [1] 0 0
Up to approximately 9 months
Secondary outcome [2] 0 0
The proportion of subjects who have a sustained virologic response (SVR; i.e., HCV RNA concentration below the lower limit of quantitation [<LLOQ; <25 IU/mL]) at 4 weeks after the last planned dose of treatment (SVR4)
Timepoint [2] 0 0
Up to 20 Weeks
Secondary outcome [3] 0 0
The proportion of subjects who have an SVR at 12 weeks after the last planned dose of treatment (SVR12)
Timepoint [3] 0 0
Up to 28 weeks
Secondary outcome [4] 0 0
The proportion of subjects who have an SVR at 44 weeks after the last planned dose of treatment (SVR24)
Timepoint [4] 0 0
Up to 40 weeks
Secondary outcome [5] 0 0
The proportion of subjects who have virologic relapse
Timepoint [5] 0 0
Up to 64 weeks
Secondary outcome [6] 0 0
The proportion of subjects who have virologic breakthrough
Timepoint [6] 0 0
Up to 16 weeks
Secondary outcome [7] 0 0
The amino acid sequence of the nonstructural NS5A and NS5B proteins in subjects who have treatment failure
Timepoint [7] 0 0
Up to 64 weeks
Secondary outcome [8] 0 0
The proportion of subjects who achieve SVR12 by HCV genotype 1 subtype (1a versus non-1a)
Timepoint [8] 0 0
Up to 28 weeks
Secondary outcome [9] 0 0
The proportion of subjects who achieve SVR12 by IL-28B genotype (CC versus non-CC)
Timepoint [9] 0 0
Up to 28 weeks

Eligibility
Key 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
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Other
Allocation to intervention
Not applicable
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
2/09/2013
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
26/08/2014
Sample size
Target
Accrual to date
Final
18
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Michigan
Country [3] 0 0
United States of America
State/province [3] 0 0
North Carolina
Country [4] 0 0
Brazil
State/province [4] 0 0
RJ
Country [5] 0 0
Brazil
State/province [5] 0 0
RS
Country [6] 0 0
Canada
State/province [6] 0 0
Quebec
Country [7] 0 0
Cyprus
State/province [7] 0 0
Nicosia
Country [8] 0 0
Korea, Republic of
State/province [8] 0 0
Seoul
Country [9] 0 0
New Zealand
State/province [9] 0 0
Auckland
Country [10] 0 0
New Zealand
State/province [10] 0 0
Christchurch

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Hoffmann-La Roche
Address
Country

Ethics approval
Ethics application status

Summary
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).
Trial website
https://clinicaltrials.gov/study/NCT01844674
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trials
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT01844674