A Pharmacokinetics (PK) Study to Investigate the Effect o... | NCT01765543

NCT01765543

ID	Type	Description	Link
2012-003142-33	EudraCT Number

Status Module

Sponsor/Collaborators Module

Oversight Module

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No data is available for this block.

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Vemurafenib + Rifampin	Experimental	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 Drug: Vemurafenib

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Rifampin	Drug	Rifampin at a dose of 600 mg as capsules orally once daily will be administered from Days 8 through 23 (Periods B and C).	Vemurafenib + Rifampin

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Area Under the Plasma Concentration Time-curve From Zero to the Last Measurable Concentration Time Point (AUClast) of Vemurafenib	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 (mcgh/mL).	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)
Area Under the Plasma Concentration Time-curve From Zero to Extrapolated Infinite Time (AUC[0-inf]) of Vemurafenib	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.	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)
Maximum Observed Plasma Concentration (Cmax) of Vemurafenib	Cmax is the maximum observed plasma vemurafenib concentration, presented in microgram per milliliter (mcg/mL).	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)

Other Outcomes

Measure	Description	Time Frame
Time to Reach Cmax (Tmax) of Vemurafenib	Tmax is the time from vemurafenib administration to reach Cmax for 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 (t1/2) of Vemurafenib

Eligibility Module

Eligibility Criteria

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/Locations Module

Name	Affiliation	Role
Clinical Trials	Hoffmann-La Roche	Study Director

References Module

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No data is available for this block.

IPD Sharing Statement Module

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No data is available for this block.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Vemurafenib + Rifampin (All Periods)	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).

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

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No data is available for this block.

Document Section

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No data is available for this block.

Derived Section

Miscellaneous Info Module

Submission Tracking

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No data is available for this block.

Condition Browse Module

Intervention Browse Module

Masking Info

The intent-to-treat (ITT) population included all participants who were enrolled in the study.

Arm/Group Information

ID	Title	Description
BG000	Vemurafenib + Rifampin (All Periods)	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).

Units	Counts
Participants	BG00027

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	OG000125± 101.4 OG00176.7± 75.3

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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.					Geometric Mean Ratio	0.614			2-Sided	90	0.484	0.780				No	Superiority or Other

Primary

Area Under the Plasma Concentration Time-curve From Zero to Extrapolated Infinite Time (AUC[0-inf]) of Vemurafenib

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.

PK parameter population

Posted

Geometric Mean

Geometric Coefficient of Variation

mcg*h/mL

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)

ID	Title	Description
OG000	Vemurafenib (Intervention Period A)	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.
OG001	Vemurafenib + Rifampin (Intervention Period C)	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.

Units	Counts

Primary

Maximum Observed Plasma Concentration (Cmax) of Vemurafenib

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

PK parameter population

Posted

Geometric Mean

Geometric Coefficient of Variation

mcg/mL

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)

ID	Title	Description
OG000	Vemurafenib (Intervention Period A)	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.
OG001	Vemurafenib + Rifampin (Intervention Period C)	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.

Units	Counts
Participants

Other Pre-specified

Time to Reach Cmax (Tmax) of Vemurafenib

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

PK parameter population

Posted

Median

Full Range

hours

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)

ID	Title	Description
OG000	Vemurafenib (Intervention Period A)	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.
OG001	Vemurafenib + Rifampin (Intervention Period C)	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.

Units	Counts
Participants

Other Pre-specified

Plasma Elimination Half Life (t1/2) of Vemurafenib

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

PK parameter population

Posted

Mean

Standard Deviation

hours

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)

ID	Title	Description
OG000	Vemurafenib (Intervention Period A)	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.
OG001	Vemurafenib + Rifampin (Intervention Period C)	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.

Units	Counts
Participants

Other Pre-specified

Plasma Apparent Clearance (CL/F) of Vemurafenib

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.

PK parameter population

Posted

Geometric Mean

Geometric Coefficient of Variation

liters/hour

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)

ID	Title	Description
OG000	Vemurafenib (Intervention Period A)	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.
OG001	Vemurafenib + Rifampin (Intervention Period C)	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.

Units	Counts

Other Pre-specified

Area Under the Plasma Concentration Time-curve From Zero to 168 Hours [AUC(0-168)] of Vemurafenib

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.

PK parameter population

Posted

Geometric Mean

Geometric Coefficient of Variation

mcg*h/mL

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)

ID	Title	Description
OG000	Vemurafenib (Intervention Period A)	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.
OG001	Vemurafenib + Rifampin (Intervention Period C)	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.

Units	Counts

Other Pre-specified

Percent Extrapolated AUC(0-inf) (AUCpeo) of Vemurafenib

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).

PK parameter population

Posted

Geometric Mean

Geometric Coefficient of Variation

percent AUC

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)

ID	Title	Description
OG000	Vemurafenib (Intervention Period A)	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.
OG001	Vemurafenib + Rifampin (Intervention Period C)	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.

Arm/Groups

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Vemurafenib (Intervention Period A)	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.	0	27	4	27
EG001	Rifampin (Intervention Period B)	Participants received rifampin alone at a dose of 600 mg as capsules orally once daily from Days 8 through 16.	0	26	8	26
EG002	Vemurafenib + Rifampin (Intervention Period C)	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.	2	25	5	25
EG003	Vemurafenib + Rifampin (All Periods)	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).	2	27	12	27

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Cardiac arrest	Cardiac disorders	MedDRA (18.1)	Non-systematic Assessment		EG0000 affected27 at risk EG0010 affected26 at risk EG0021 affected25 at risk EG0031 affected27 at risk
Confusional state	Psychiatric disorders	MedDRA (18.1)	Non-systematic Assessment		EG0000 affected27 at risk EG0010 affected26 at risk EG0021 affected25 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Constipation	Gastrointestinal disorders	MedDRA (18.1)	Non-systematic Assessment	EG0000 affected27 at risk EG0012 affected26 at risk EG0020 affected25 at risk EG0032 affected27 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA (18.1)	Non-systematic Assessment	EG0001 affected27 at risk EG0010 affected26 at risk EG0021 affected25 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA (18.1)	Non-systematic Assessment	EG0000 affected27 at risk EG0010 affected26 at risk EG0022 affected25 at risk EG003
Decreased appetite	Metabolism and nutrition disorders	MedDRA (18.1)	Non-systematic Assessment	EG0000 affected27 at risk EG0011 affected26 at risk EG0021 affected25 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA (18.1)	Non-systematic Assessment	EG0001 affected27 at risk EG0012 affected26 at risk EG0020 affected25 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA (18.1)	Non-systematic Assessment	EG0001 affected27 at risk EG0010 affected26 at risk EG0021 affected25 at risk EG003
Headache	Nervous system disorders	MedDRA (18.1)	Non-systematic Assessment	EG0002 affected27 at risk EG0012 affected26 at risk EG0023 affected25 at risk EG003
Chromaturia	Renal and urinary disorders	MedDRA (18.1)	Non-systematic Assessment	EG0000 affected27 at risk EG0015 affected26 at risk EG0020 affected25 at risk EG003

ID	Term
D008545	Melanoma
D009369	Neoplasms

Ancestor Terms

ID	Term
D018358	Neuroendocrine Tumors
D017599	Neuroectodermal Tumors
D009373	Neoplasms, Germ Cell and Embryonal
D009370	Neoplasms by Histologic Type
D009380	Neoplasms, Nerve Tissue
D018326	Nevi and Melanomas
D012878	Skin Neoplasms
D009371	Neoplasms by Site
D012871	Skin Diseases
D017437	Skin and Connective Tissue Diseases

ID	Term
D012293	Rifampin
D000077484	Vemurafenib

Ancestor Terms

ID	Term
D012294	Rifamycins
D006576	Heterocyclic Compounds, 4 or More Rings
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds
D047029	Lactams, Macrocyclic
D047028	Macrocyclic Compounds
D011083	Polycyclic Compounds
D013449	Sulfonamides
D000577	Amides
D009930	Organic Chemicals
D013450	Sulfones
D013457	Sulfur Compounds
D007211	Indoles
D006574	Heterocyclic Compounds, 2-Ring

Facility	Status	City	State	ZIP	Country	Contacts
		Rogers	Arkansas	72758	United States