Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Anti-Arrhythmia Agents

Cardiotonic Agents

All Drugs and Chemicals

Antineoplastic Agents

Digoxin

Vemurafenib

Enzyme Inhibitors

Protective Agents

Protein Kinase Inhibitors

Single oral dose of digoxin 0.25 mg tablet on Day 1 in Period A, followed by vemurafenib 960 mg tablet orally BID from Day 8 to Day 28 in Period B, and then single oral dose of digoxin 0.25 mg on Day 29, and vemurafenib 960 mg orally BID from Day 29 to Day 35 in Period C.

Participants received single oral dose of digoxin 0.25 mg tablet on Day 1 and Day 29.

Participants received vemurafenib 960 mg tablet orally BID from Day 8 to Day 35.

Clinical Trials

This open-label, multi-center, three-period, one sequence study will investigate the effect of vemurafenib on the pharmacokinetics of digoxin in patients 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. Patients will receive multiple doses of vemurafenib in Periods B and C and a single dose of digoxin in Periods A and C. Eligible patients will have the option to continue treatment with vemurafenib as part of an extension study (NCT01739764). The anticipated time on study treatment is approximately 36 days.

A Pharmacokinetics Study to Investigate the Effect of Vemurafenib on Digoxin in Patients With BRAFV600 Mutation-Positive Metastatic Melanoma

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 Digoxin In Patients With BRAFV600 Mutation-Positive Metastatic Malignancy

AUClast = Area under the plasma-concentration time curve from time zero to the last measurable plasma concentration which is presented in hour\*nanogram per milliliter (hour\*ng/mL). Hour 0 (H0) signified pre-dose sampling.

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

Hoffmann-La Roche

Single oral dose of digoxin 0.25 mg tablet on Day 1.

Period A

Vemurafenib 960 mg orally BID from Day 8 to Day 28.

Period B

Single oral dose of digoxin 0.25 mg on Day 29, and vemurafenib 960 mg orally BID from Day 29 to Day 35.

Period C

Single oral dose of digoxin 0.25 mg tablet on Day 1 in Period A, followed by vemurafenib 960 mg orally BID from Day 8 to Day 28 in Period B, and then single oral dose of digoxin 0.25 mg on Day 29, and vemurafenib 960 mg orally BID from Day 29 to Day 35 in Period C.

Digoxin: Participants received single oral dose of digoxin 0.25 mg tablet on Day 1 and Day 29.

Vemurafenib: Participants received vemurafenib 960 mg tablet orally BID from Day 8 to Day 35.

Vemurafenib + Digoxin

Age, Continuous

Sex: Female, Male

Medical Communications

Participants received single oral dose of digoxin 0.25 mg tablet on Day 1.

Period A (Digoxin)

Participants received single oral dose of digoxin 0.25 mg tablet on Day 29 and vemurafenib 960 mg tablet orally BID from Day 29 to Day 35.

Period C (Digoxin + Vemurafenib)

PK Population included participants for whom PK data were collected.

Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUClast) of Digoxin

PK Population. Number of participants analysed = participants evaluable for the analysis.

Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Digoxin

Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC24) of Digoxin

Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC168) of Digoxin

Maximum Plasma Concentration (Cmax) of Digoxin

Time to Maximum Plasma Concentration (Tmax) of Digoxin

Terminal Half-Life (t1/2) of Digoxin

Apparent Clearance (CL/F) of Digoxin

Anticoagulants

Phenprocoumon

phenprocoumon

vemurafenib

This open-label, multicenter, parallel study will evaluate the effect of multiple doses of vemurafenib on the pharmacokinetics of a single dose of phenprocoumon in patients with BRAFV600 mutation-positive metastatic malignancies. Patients will be randomized to receive either treatment A: a single oral dose of phenprocoumon 6 mg on Day 1 (Eligible patients will have the option to continue treatment with vemurafenib as part of an extension study (NCT01739764).), or treatment B: vemurafenib 960 mg orally twice daily on Days 1-29 plus a single oral dose of phenprocoumon 6 mg on Day 22 (with the option to receive vemurafenib in the extension study after completion of pharmacokinetic assessments).

A Study of the Effect of Vemurafenib on the Pharmacokinetics of Phenprocoumon in Patients With BRAFV600 Mutation-Positive Metastatic Malignancy

A PHASE I, OPEN-LABEL, MULTICENTER, RANDOMINZED, PARALELL STUDY TO INVESTIGATE THE EFFECT OF VEMURAFENIB ON THE PHARMACOKINETICS OF A SINGLE ORAL DOSE OF PHENPROCOUMON IN PATIENTS WITH BRAFV600 MUTATION-POSITIVE METASTATIC MALIGNANCY

Anti-Infective Agents

Ketoconazole

Clotrimazole

Miconazole

Antifungal Agents

Cytochrome P-450 Enzyme Inhibitors

Hormones

Hormone Antagonists

Cytochrome P-450 CYP3A Inhibitors

multiple doses of ketoconazole in Period B and C

ketoconazole

single dose of vemurafenib in Period A and C

This open-label, multi-center, three-period, one sequence study will investigate the effect of ketoconazole on the pharmacokinetics of vemurafenib in patients 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. Patients will receive a single dose of vemurafenib in Periods A and C and multiple doses of ketoconazole in Periods B and C. Eligible patients will have the option to continue treatment with vemurafenib as part of an extension study (NCT01739764). The anticipated time on study treatment is approximately 19 days.

A Pharmacokinetics Study to Investigate the Effect of Ketoconazole on Vemurafenib in Patients With BRAFV600 Mutation-Positive Metastatic Melanoma

A Phase I, Open-Label, Multicenter, Three-Period, One-Sequence Study To Investigate The Effect Of Ketoconazole On The Pharmacokinetics Of A Single Oral Dose Of 960 Mg Of Vemurafenib

Rifampin

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antitubercular Agents

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).

Rifampin at a dose of 600 mg as capsules orally once daily will be administered from Days 8 through 23 (Periods B and C).

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).

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).

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

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

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

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

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.

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.

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).

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).

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.

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

The safety analysis population included all participants who received at least 1 dose of vemurafenib.

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.

Vemurafenib (Intervention Period A)

Participants received rifampin alone at a dose of 600 mg as capsules orally once daily from Days 8 through 16.

Rifampin (Intervention Period B)

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.

Vemurafenib + Rifampin (Intervention Period C)

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).

Vemurafenib + Rifampin (All Periods)

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

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.

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.

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.

Area Under the Plasma Concentration Time-curve From Zero to the Last Measurable Concentration Time Point (AUClast) of Vemurafenib

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.

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

Maximum Observed Plasma Concentration (Cmax) of Vemurafenib

Time to Reach Cmax (Tmax) of Vemurafenib

Plasma Elimination Half Life (t1/2) of Vemurafenib

Plasma Apparent Clearance (CL/F) of Vemurafenib

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

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

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).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Pharmacokinetics Study to Investigate the Effect of Vemurafenib on Digoxin in Patients With BRAFV600 Mutation-Positive Metastatic Melanoma	NCT01765569	Malignant Melan...	Digoxin Vemurafenib	18 Years -	Hoffmann-La Roche
A Study of the Effect of Vemurafenib on the Pharmacokinetics of Phenprocoumon in Patients With BRAFV600 Mutation-Positive Metastatic Malignancy	NCT01849666	Malignant Melan...	phenprocoumon vemurafenib	18 Years - 70 Years	Hoffmann-La Roche
A Pharmacokinetics Study to Investigate the Effect of Ketoconazole on Vemurafenib in Patients With BRAFV600 Mutation-Positive Metastatic Melanoma	NCT01765556	Malignant Melan...	ketoconazole vemurafenib	18 Years -	Hoffmann-La Roche
A Pharmacokinetics (PK) Study to Investigate the Effect of Rifampin on PK of Vemurafenib (Zelboraf)	NCT01765543	Malignant Melan...	Rifampin Vemurafenib	18 Years -	Hoffmann-La Roche

Spots Global Cancer Trial Database for malignant melanoma, neoplasms