A Pharmacokinetics Study to Investigate the Effect of Vemurafenib on Digoxin in Patients With BRAFV600 Mutation-Positive Metastatic Melanoma
- Registration Number
- NCT01765569
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 29
Inclusion Criteria
- Male or female patients >= 18 years old
- Patients with either unresectable Stage IIIc or Stage IV metastatic melanoma positive for the BRAFV600 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 DNA sequencing method, and who have no acceptable standard treatment options
- Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
- Life expectancy >= 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 patients of childbearing potential and male patients with partners of childbearing potential must agree to always use two 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
- 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 QTc > 450 ms
- Current digoxin therapy or anticipated requirement to take digoxin therapy during the study
- Active central nervous system lesions
- Uncontrolled or poorly controlled diabetes
- Current severe, uncontrolled systemic disease
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Vemurafenib + Digoxin Digoxin 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. Vemurafenib + Digoxin Vemurafenib 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.
- Primary Outcome Measures
Name Time Method Time to Maximum Plasma Concentration (Tmax) of Digoxin Hour [H] 0, 0.5, 1, 2, 3, 4, 6, 8, 10-12 (Day [D] 1), 24, 30-32 (D2), 48 (D3), 72 (D4), 96 (D5), 168 (D8) post-digoxin dose; H0, 0.5, 1, 2, 3, 4, 6, 8, and 10-12H (D29), 24, 30-32 (D30), 48 (D31), 72 (D32), 96 (D33), 168 (D36) post digoxin dose Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUClast) of Digoxin Hour [H] 0, 0.5, 1, 2, 3, 4, 6, 8, 10-12 (Day [D] 1), 24, 30-32 (D2), 48 (D3), 72 (D4), 96 (D5), 168 (D8) post-digoxin dose; H0, 0.5, 1, 2, 3, 4, 6, 8, and 10-12H (D29), 24, 30-32 (D30), 48 (D31), 72 (D32), 96 (D33), 168 (D36) post digoxin dose 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.
Maximum Plasma Concentration (Cmax) of Digoxin Hour [H] 0, 0.5, 1, 2, 3, 4, 6, 8, 10-12 (Day [D] 1), 24, 30-32 (D2), 48 (D3), 72 (D4), 96 (D5), 168 (D8) post-digoxin dose; H0, 0.5, 1, 2, 3, 4, 6, 8, and 10-12H (D29), 24, 30-32 (D30), 48 (D31), 72 (D32), 96 (D33), 168 (D36) post digoxin dose Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Digoxin Hour [H] 0, 0.5, 1, 2, 3, 4, 6, 8, 10-12 (Day [D] 1), 24, 30-32 (D2), 48 (D3), 72 (D4), 96 (D5), 168 (D8) post-digoxin dose; H0, 0.5, 1, 2, 3, 4, 6, 8, and 10-12H (D29), 24, 30-32 (D30), 48 (D31), 72 (D32), 96 (D33), 168 (D36) post digoxin dose Apparent Clearance (CL/F) of Digoxin Hour [H] 0, 0.5, 1, 2, 3, 4, 6, 8, 10-12 (Day [D] 1), 24, 30-32 (D2), 48 (D3), 72 (D4), 96 (D5), 168 (D8) post-digoxin dose; H0, 0.5, 1, 2, 3, 4, 6, 8, and 10-12H (D29), 24, 30-32 (D30), 48 (D31), 72 (D32), 96 (D33), 168 (D36) post digoxin dose 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.
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC24) of Digoxin Hour [H] 0, 0.5, 1, 2, 3, 4, 6, 8, 10-12 (Day [D] 1), 24, 30-32 (D2), 48 (D3), 72 (D4), 96 (D5), 168 (D8) post-digoxin dose; H0, 0.5, 1, 2, 3, 4, 6, 8, and 10-12H (D29), 24, 30-32 (D30), 48 (D31), 72 (D32), 96 (D33), 168 (D36) post digoxin dose Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC168) of Digoxin Hour [H] 0, 0.5, 1, 2, 3, 4, 6, 8, 10-12 (Day [D] 1), 24, 30-32 (D2), 48 (D3), 72 (D4), 96 (D5), 168 (D8) post-digoxin dose; H0, 0.5, 1, 2, 3, 4, 6, 8, and 10-12H (D29), 24, 30-32 (D30), 48 (D31), 72 (D32), 96 (D33), 168 (D36) post digoxin dose Terminal Half-Life (t1/2) of Digoxin Hour [H] 0, 0.5, 1, 2, 3, 4, 6, 8, 10-12 (Day [D] 1), 24, 30-32 (D2), 48 (D3), 72 (D4), 96 (D5), 168 (D8) post-digoxin dose; H0, 0.5, 1, 2, 3, 4, 6, 8, and 10-12H (D29), 24, 30-32 (D30), 48 (D31), 72 (D32), 96 (D33), 168 (D36) post digoxin dose
- Secondary Outcome Measures
Name Time Method