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

Malignant Melanoma, Neoplasms Clinical Trial

Official 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 Digoxin In Patients With BRAFV600 Mutation-Positive Metastatic Malignancy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01765569
• Other study ID #: GO28394
• Secondary ID: 2012-003459-13
• Status: Completed
• Phase: Phase 1
• First received: January 9, 2013
• Last updated: August 24, 2015
• Start date: July 2013
• Est. completion date: June 2014

Study information

• Verified date: August 2015
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 29
• Est. completion date: June 2014
• Est. primary completion date: June 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Malignant Melanoma, Neoplasms
• Melanoma

Intervention

Drug:
• 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.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

Belarus,  Israel,  Korea, Republic of,  Russian Federation,  South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUClast) of Digoxin	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.	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	Apparent Clearance (CL/F) of Digoxin	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.	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	No