A Pharmacokinetics (PK) Study to Investigate the Effect of Rifampin on PK of Vemurafenib (Zelboraf)

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01765543
• Collaborator: (none)
• Enrollment: 27
• Locations: 15
• Arm: 1
• Duration (Months): 28
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This open-label, multi-center, three-period, one-sequence study will investigate the effect of rifampin on the PK of vemurafenib in participants with unresectable BRAFV600-mutation positive metastatic melanoma or other malignant tumor type that harbors a V600-activating mutation of BRAF without acceptable standard treatment options. Eligible participants will have the option to continue treatment with vemurafenib as part of an extension study GO28399 (NCT01739764).

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma, Neoplasms	Drug: Rifampin; Drug: Vemurafenib	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I, Open-Label, Multicenter, Three-Period, One-Sequence Study to Investigate the Effect of Rifampin on the Pharmacokinetics of a Single Oral Dose of 960 mg of Vemurafenib
• Study Start Date: Jul 1, 2013
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Vemurafenib + Rifampin There will be 3 intervention periods in the study: Period A (Days 1 to 7), Period B (Days 8 to 16), and Period C (Days 17 to 24). Participants, after an overnight fast of at least 10 hours, will receive vemurafenib at a dose of 960 milligrams (mg) as film-coated tablets orally alone on Day 1 (Period A); with rifampin (at a dose of 600 mg as capsules orally) on Day 17 (Period C); and rifampin alone at a dose of 600 mg as capsules orally once daily will be administered from Days 8 through 16 (Period B) and from Days 18 through 23 (Period C).

Drug: Rifampin; Rifampin at a dose of 600 mg as capsules orally once daily will be administered from Days 8 through 23 (Periods B and C).; Drug: Vemurafenib; Participants, after an overnight fast of at least 10 hours, will receive vemurafenib at a dose of 960 mg as film-coated tablets orally on Day 1 (Period A) and on Day 17 (Period C).; Other Names: RO5185426, Zelboraf

Outcome Measures

Primary Outcome Measures

1. Area Under the Plasma Concentration Time-curve From Zero to the Last Measurable Concentration Time Point (AUClast) of Vemurafenib [Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)]

   AUClast is the area under the vemurafenib plasma concentration versus time curve from time zero to the time of last measured concentration of vemurafenib (Tlast). Area under the curve (AUC) is a measure of the plasma concentration of a drug over time. AUClast is presented in micrograms times (*) hour per milliliter (mcg*h/mL).

2. Area Under the Plasma Concentration Time-curve From Zero to Extrapolated Infinite Time (AUC[0-inf]) of Vemurafenib [Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)]

   AUC(0-inf) is the AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of a drug over time. AUC(0-inf) is presented in mcg*h/mL.

3. Maximum Observed Plasma Concentration (Cmax) of Vemurafenib [Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)]

   Cmax is the maximum observed plasma vemurafenib concentration, presented in microgram per milliliter (mcg/mL).

Other Outcome Measures

1. Time to Reach Cmax (Tmax) of Vemurafenib [Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)]

   Tmax is the time from vemurafenib administration to reach Cmax for vemurafenib.

2. Plasma Elimination Half Life (t1/2) of Vemurafenib [Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)]

   Plasma elimination half-life is the time measured during drug elimination phase for the plasma drug concentration to decrease by one half.

3. Plasma Apparent Clearance (CL/F) of Vemurafenib [Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)]

   Clearance of a drug is a measure of the rate at which a drug is removed (metabolized or eliminated by normal biological processes) from the blood. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.

4. Area Under the Plasma Concentration Time-curve From Zero to 168 Hours [AUC(0-168)] of Vemurafenib [Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)]

   AUC(0-168) is the AUC from time zero (pre-dose) to 168 hours (time point for last blood sample collection). AUC is a measure of the plasma concentration of a drug over time. AUC(0-168) is presented in mcg*h/mL.

5. Percent Extrapolated AUC(0-inf) (AUCpeo) of Vemurafenib [Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)]

   The AUCpeo, that is, percent area obtained after extrapolation from Tlast to infinity is calculated by using the formula AUCpeo = 100*(AUC[0-inf] minus AUC[0-last])/AUC(0-inf). This parameter provides information about what percentage of the theoretical curve AUC(0-inf) is possible to determine experimentally (AUC0-last).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participants with either unresectable Stage IIIc or Stage IV metastatic melanoma positive for the BRAF V600 mutation or other malignant tumor type that harbors a V600-activating mutation of BRAF, as determined by results of cobas® 4800 BRAF V600 mutation test or a Deoxyribonucleic acid (DNA) sequencing method, and who have no acceptable standard treatment options

• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2

• Life expectancy of greater than or equal to (>/=) 12 weeks

• Full recovery from the effects of any major surgery or significant traumatic injury within 14 days prior to the first dose of study treatment

• Adequate hematologic and end organ function

• Female participants of childbearing potential and male participants with partners of childbearing potential must agree to always use 2 effective methods of contraception

• Negative serum pregnancy test within 7 days prior to commencement of dosing in women of childbearing potential

Exclusion Criteria:

• Prior treatment with vemurafenib or other BRAF inhibitor within 42 days of first dose of study drug

• Requirement for immediate or urgent treatment with daily vemurafenib and for whom the intermittent schedule of vemurafenib employed during the 24-day period for this trial is not clinically acceptable

• Allergy or hypersensitivity to components of the vemurafenib formulation

• Experimental therapy within 4 weeks prior to first dose of study drug

• Major surgical procedure or significant traumatic injury within 14 days prior to first dose of study drug, or anticipation of the need for major surgery during study treatment

• Prior anti-cancer therapy within 28 days before the first dose of study drug

• History of clinically significant cardiac or pulmonary dysfunction

• History of symptomatic congestive heart failure of any New York Heart Association class or serious cardiac arrhythmia requiring treatment

• History of myocardial infarction within 6 months prior to first dose of study drug

• Current dyspnea at rest, owing to complications of advanced malignancy or any requirement for supplemental oxygen to perform activities of daily living

• History of congenital long QT syndrome or corrected QT interval (QTc) greater than (>) 450 milliseconds

• Active central nervous system lesions

• Uncontrolled or poorly controlled diabetes

• Current severe, uncontrolled systemic disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Rogers	Arkansas	United States	72758
2		Pleasant Hill	California	United States	94523
3		Middletown	Ohio	United States	45042
4		Dallas	Texas	United States	75246
5		Porto Alegre	RS	Brazil	90020-090
6		Porto Alegre	RS	Brazil	90035-003
7		Porto Alegre	RS	Brazil	90840-440
8		Varazdin		Croatia	42000
9		Zagreb		Croatia	10000
10		Alexandria		Egypt	21131
11		Cairo		Egypt	11796
12		Dakahlia		Egypt	324
13		Tanta		Egypt
14		Cape Town		South Africa	7570
15		Port Elizabeth		South Africa	6045

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01765543
• Other Study ID Numbers: GO28052; 2012-003142-33
• First Posted: Jan 10, 2013
• Last Update Posted: Dec 15, 2016
• Last Verified: Oct 1, 2016

• Additional relevant MeSH terms: Melanoma; Rifampin; Vemurafenib

Study Results

Participant Flow

Pre-assignment Detail	A total of 27 participants were enrolled into the study.

Arm/Group Title	Vemurafenib + Rifampin (All Periods)
Arm/Group Description	There were 3 intervention periods in the study: Period A (Days 1 to 7), Period B (Days 8 to 16), and Period C (Days 17 to 24). Participants, after an overnight fast of at least 10 hours, received vemurafenib (Zelboraf) at a dose of 960 milligrams (mg) as film-coated tablets orally alone on Day 1 (Period A); with rifampin (at a dose of 600 mg as capsules orally) on Day 17 (Period C); and rifampin alone at a dose of 600 mg as capsules orally once daily was administered from Days 8 through 16 (Period B) and from Days 18 through 23 (Period C).
Period Title: Overall Study
STARTED	27
COMPLETED	24
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Vemurafenib + Rifampin (All Periods)
Arm/Group Description	There were 3 intervention periods in the study: Period A (Days 1 to 7), Period B (Days 8 to 16), and Period C (Days 17 to 24). Participants, after an overnight fast of at least 10 hours, received vemurafenib at a dose of 960 mg as film-coated tablets orally alone on Day 1 (Period A); with rifampin (at a dose of 600 mg as capsules orally) on Day 17 (Period C); and rifampin alone at a dose of 600 mg as capsules orally once daily was administered from Days 8 through 16 (Period B) and from Days 18 through 23 (Period C).
Overall Participants	27
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.9 (13.0)
Sex: Female, Male (Count of Participants)
Female	9 33.3%
Male	18 66.7%

Outcome Measures

1. Primary Outcome

Title	Area Under the Plasma Concentration Time-curve From Zero to the Last Measurable Concentration Time Point (AUClast) of Vemurafenib
Description	AUClast is the area under the vemurafenib plasma concentration versus time curve from time zero to the time of last measured concentration of vemurafenib (Tlast). Area under the curve (AUC) is a measure of the plasma concentration of a drug over time. AUClast is presented in micrograms times (*) hour per milliliter (mcg*h/mL).
Time Frame	Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)

Outcome Measure Data

Analysis Population Description

The pharmacokinetics (PK) parameter population included all participants who received both scheduled doses of vemurafenib and who provided adequate PK assessments to calculate important PK parameters.

Arm/Group Title	Vemurafenib (Intervention Period A)	Vemurafenib + Rifampin (Intervention Period C)
Arm/Group Description	Participants, after an overnight fast of at least 10 hours, received vemurafenib alone at a dose of 960 mg as film-coated tablets orally on Day 1.	Participants, after an overnight fast of at least 10 hours, received vemurafenib at a dose of 960 mg as film-coated tablets orally along with rifampin at a dose of 600 mg as capsules orally on Day 17 and rifampin alone at a dose of 600 mg as capsules orally once daily was administered from Days 18 through 23.
Measure Participants	23	23
Geometric Mean (Geometric Coefficient of Variation) [mcg*h/mL]	125 (101.4)	76.7 (75.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vemurafenib (Intervention Period A), Vemurafenib + Rifampin (Intervention Period C)
	Comments	Analysis of variance (ANOVA) was applied to the log-transformed PK parameters, and then back transformed to provide geometric mean ratio (Period C/Period A) and confidence intervals.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	0.614
	Confidence Interval	(2-Sided) 90%; 0.484 to 0.780
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Area Under the Plasma Concentration Time-curve From Zero to Extrapolated Infinite Time (AUC[0-inf]) of Vemurafenib
Description	AUC(0-inf) is the AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of a drug over time. AUC(0-inf) is presented in mcg*h/mL.
Time Frame	Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)

Outcome Measure Data

Analysis Population Description

PK parameter population

Arm/Group Title	Vemurafenib (Intervention Period A)	Vemurafenib + Rifampin (Intervention Period C)
Arm/Group Description	Participants, after an overnight fast of at least 10 hours, received vemurafenib alone at a dose of 960 mg as film-coated tablets orally on Day 1.	Participants, after an overnight fast of at least 10 hours, received vemurafenib at a dose of 960 mg as film-coated tablets orally along with rifampin at a dose of 600 mg as capsules orally on Day 17 and rifampin alone at a dose of 600 mg as capsules orally once daily was administered from Days 18 through 23.
Measure Participants	23	23
Geometric Mean (Geometric Coefficient of Variation) [mcg*h/mL]	131 (104.2)	78.1 (74.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vemurafenib (Intervention Period A), Vemurafenib + Rifampin (Intervention Period C)
	Comments	ANOVA was applied to the log-transformed PK parameters, and then back transformed to provide geometric mean ratio (Period C/Period A) and confidence intervals.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	0.596
	Confidence Interval	(2-Sided) 90%; 0.469 to 0.759
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of Vemurafenib
Description	Cmax is the maximum observed plasma vemurafenib concentration, presented in microgram per milliliter (mcg/mL).
Time Frame	Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)

Outcome Measure Data

Analysis Population Description

PK parameter population

Arm/Group Title	Vemurafenib (Intervention Period A)	Vemurafenib + Rifampin (Intervention Period C)
Arm/Group Description	Participants, after an overnight fast of at least 10 hours, received vemurafenib alone at a dose of 960 mg as film-coated tablets orally on Day 1.	Participants, after an overnight fast of at least 10 hours, received vemurafenib at a dose of 960 mg as film-coated tablets orally along with rifampin at a dose of 600 mg as capsules orally on Day 17 and rifampin alone at a dose of 600 mg as capsules orally once daily was administered from Days 18 through 23.
Measure Participants	23	23
Geometric Mean (Geometric Coefficient of Variation) [mcg/mL]	4.45 (63.3)	4.95 (59.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vemurafenib (Intervention Period A), Vemurafenib + Rifampin (Intervention Period C)
	Comments	ANOVA was applied to the log-transformed PK parameters, and then back transformed to provide geometric mean ratio (Period C/Period A) and confidence intervals.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 90%; 0.908 to 1.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Other Pre-specified Outcome

Title	Time to Reach Cmax (Tmax) of Vemurafenib
Description	Tmax is the time from vemurafenib administration to reach Cmax for vemurafenib.
Time Frame	Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)

Outcome Measure Data

Analysis Population Description

PK parameter population

Arm/Group Title	Vemurafenib (Intervention Period A)	Vemurafenib + Rifampin (Intervention Period C)
Arm/Group Description	Participants, after an overnight fast of at least 10 hours, received vemurafenib alone at a dose of 960 mg as film-coated tablets orally on Day 1.	Participants, after an overnight fast of at least 10 hours, received vemurafenib at a dose of 960 mg as film-coated tablets orally along with rifampin at a dose of 600 mg as capsules orally on Day 17 and rifampin alone at a dose of 600 mg as capsules orally once daily was administered from Days 18 through 23.
Measure Participants	23	23
Median (Full Range) [hours]	4.00	4.00

5. Other Pre-specified Outcome

Title	Plasma Elimination Half Life (t1/2) of Vemurafenib
Description	Plasma elimination half-life is the time measured during drug elimination phase for the plasma drug concentration to decrease by one half.
Time Frame	Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)

Outcome Measure Data

Analysis Population Description

PK parameter population

Arm/Group Title	Vemurafenib (Intervention Period A)	Vemurafenib + Rifampin (Intervention Period C)
Arm/Group Description	Participants, after an overnight fast of at least 10 hours, received vemurafenib alone at a dose of 960 mg as film-coated tablets orally on Day 1.	Participants, after an overnight fast of at least 10 hours, received vemurafenib at a dose of 960 mg as film-coated tablets orally along with rifampin at a dose of 600 mg as capsules orally on Day 17 and rifampin alone at a dose of 600 mg as capsules orally once daily was administered from Days 18 through 23.
Measure Participants	23	23
Mean (Standard Deviation) [hours]	29.7 (17.6)	11.6 (5.24)

6. Other Pre-specified Outcome

Title	Plasma Apparent Clearance (CL/F) of Vemurafenib
Description	Clearance of a drug is a measure of the rate at which a drug is removed (metabolized or eliminated by normal biological processes) from the blood. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.
Time Frame	Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)

Outcome Measure Data

Analysis Population Description

PK parameter population

Arm/Group Title	Vemurafenib (Intervention Period A)	Vemurafenib + Rifampin (Intervention Period C)
Arm/Group Description	Participants, after an overnight fast of at least 10 hours, received vemurafenib alone at a dose of 960 mg as film-coated tablets orally on Day 1.	Participants, after an overnight fast of at least 10 hours, received vemurafenib at a dose of 960 mg as film-coated tablets orally along with rifampin at a dose of 600 mg as capsules orally on Day 17 and rifampin alone at a dose of 600 mg as capsules orally once daily was administered from Days 18 through 23.
Measure Participants	23	23
Geometric Mean (Geometric Coefficient of Variation) [liters/hour]	7.35 (104.2)	12.3 (74.3)

7. Other Pre-specified Outcome

Title	Area Under the Plasma Concentration Time-curve From Zero to 168 Hours [AUC(0-168)] of Vemurafenib
Description	AUC(0-168) is the AUC from time zero (pre-dose) to 168 hours (time point for last blood sample collection). AUC is a measure of the plasma concentration of a drug over time. AUC(0-168) is presented in mcg*h/mL.
Time Frame	Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)

Outcome Measure Data

Analysis Population Description

PK parameter population

Arm/Group Title	Vemurafenib (Intervention Period A)	Vemurafenib + Rifampin (Intervention Period C)
Arm/Group Description	Participants, after an overnight fast of at least 10 hours, received vemurafenib alone at a dose of 960 mg as film-coated tablets orally on Day 1.	Participants, after an overnight fast of at least 10 hours, received vemurafenib at a dose of 960 mg as film-coated tablets orally along with rifampin at a dose of 600 mg as capsules orally on Day 17 and rifampin alone at a dose of 600 mg as capsules orally once daily was administered from Days 18 through 23.
Measure Participants	23	23
Geometric Mean (Geometric Coefficient of Variation) [mcg*h/mL]	126 (99.6)	78.0 (74.2)

8. Other Pre-specified Outcome

Title	Percent Extrapolated AUC(0-inf) (AUCpeo) of Vemurafenib
Description	The AUCpeo, that is, percent area obtained after extrapolation from Tlast to infinity is calculated by using the formula AUCpeo = 100*(AUC[0-inf] minus AUC[0-last])/AUC(0-inf). This parameter provides information about what percentage of the theoretical curve AUC(0-inf) is possible to determine experimentally (AUC0-last).
Time Frame	Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)

Outcome Measure Data

Analysis Population Description

PK parameter population

Arm/Group Title	Vemurafenib (Intervention Period A)	Vemurafenib + Rifampin (Intervention Period C)
Arm/Group Description	Participants, after an overnight fast of at least 10 hours, received vemurafenib alone at a dose of 960 mg as film-coated tablets orally on Day 1.	Participants, after an overnight fast of at least 10 hours, received vemurafenib at a dose of 960 mg as film-coated tablets orally along with rifampin at a dose of 600 mg as capsules orally on Day 17 and rifampin alone at a dose of 600 mg as capsules orally once daily was administered from Days 18 through 23.
Measure Participants	23	23
Geometric Mean (Geometric Coefficient of Variation) [percent AUC]	2.75 (150.4)	1.26 (95.9)

Adverse Events

Time Frame	Day 1 up to 28 days after last dose of study drug (up to 51 days overall)
Adverse Event Reporting Description	The safety analysis population included all participants who received at least 1 dose of vemurafenib.
Arm/Group Title	Vemurafenib (Intervention Period A)		Rifampin (Intervention Period B)		Vemurafenib + Rifampin (Intervention Period C)		Vemurafenib + Rifampin (All Periods)
Arm/Group Description	Participants, after an overnight fast of at least 10 hours, received vemurafenib alone at a dose of 960 mg as film-coated tablets orally on Day 1.		Participants received rifampin alone at a dose of 600 mg as capsules orally once daily from Days 8 through 16.		Participants, after an overnight fast of at least 10 hours, received vemurafenib at a dose of 960 mg as film-coated tablets orally with rifampin at a dose of 600 mg as capsules orally on Day 17 and rifampin alone at a dose of 600 mg as capsules orally once daily was administered from Days 18 through 23.		There were 3 intervention periods in the study: Period A (Days 1 to 7), Period B (Days 8 to 16), and Period C (Days 17 to 24). Participants, after an overnight fast of at least 10 hours, received vemurafenib at a dose of 960 mg as film-coated tablets orally alone on Day 1 (Period A); with rifampin (at a dose of 600 mg as capsules orally) on Day 17 (Period C); and rifampin alone at a dose of 600 mg as capsules orally once daily was administered from Days 8 through 16 (Period B) and from Days 18 through 23 (Period C).
All Cause Mortality
	Vemurafenib (Intervention Period A)		Rifampin (Intervention Period B)		Vemurafenib + Rifampin (Intervention Period C)		Vemurafenib + Rifampin (All Periods)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Vemurafenib (Intervention Period A)		Rifampin (Intervention Period B)		Vemurafenib + Rifampin (Intervention Period C)		Vemurafenib + Rifampin (All Periods)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/26 (0%)		2/25 (8%)		2/27 (7.4%)
Cardiac disorders
Cardiac arrest	0/27 (0%)		0/26 (0%)		1/25 (4%)		1/27 (3.7%)
Psychiatric disorders
Confusional state	0/27 (0%)		0/26 (0%)		1/25 (4%)		1/27 (3.7%)
Other (Not Including Serious) Adverse Events
	Vemurafenib (Intervention Period A)		Rifampin (Intervention Period B)		Vemurafenib + Rifampin (Intervention Period C)		Vemurafenib + Rifampin (All Periods)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/27 (14.8%)		8/26 (30.8%)		5/25 (20%)		12/27 (44.4%)
Gastrointestinal disorders
Constipation	0/27 (0%)		2/26 (7.7%)		0/25 (0%)		2/27 (7.4%)
Diarrhoea	1/27 (3.7%)		0/26 (0%)		1/25 (4%)		2/27 (7.4%)
Nausea	0/27 (0%)		0/26 (0%)		2/25 (8%)		2/27 (7.4%)
Metabolism and nutrition disorders
Decreased appetite	0/27 (0%)		1/26 (3.8%)		1/25 (4%)		2/27 (7.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/27 (3.7%)		2/26 (7.7%)		0/25 (0%)		3/27 (11.1%)
Pain in extremity	1/27 (3.7%)		0/26 (0%)		1/25 (4%)		2/27 (7.4%)
Nervous system disorders
Headache	2/27 (7.4%)		2/26 (7.7%)		3/25 (12%)		4/27 (14.8%)
Renal and urinary disorders
Chromaturia	0/27 (0%)		5/26 (19.2%)		0/25 (0%)		5/27 (18.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.