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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01765569
First received: January 9, 2013
Last updated: July 14, 2015
Last verified: July 2015
  Purpose

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.


Condition Intervention Phase
Malignant Melanoma, Neoplasms
Drug: Digoxin
Drug: Vemurafenib
Phase 1

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

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUClast) of Digoxin [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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). PK Population included participants that had derived PK parameters. Hour 0 (H0) signified pre-dose sampling.

  • Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Digoxin [ Time Frame: 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 ] [ Designated as safety issue: No ]
    PK Population.

  • Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC24) of Digoxin [ Time Frame: 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 ] [ Designated as safety issue: No ]
    PK Population.

  • Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC168) of Digoxin [ Time Frame: 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 ] [ Designated as safety issue: No ]
    PK Population.

  • Maximum Plasma Concentration (Cmax) of Digoxin [ Time Frame: 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 ] [ Designated as safety issue: No ]
    PK Population.

  • Time to Maximum Plasma Concentration (Tmax) of Digoxin [ Time Frame: 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 ] [ Designated as safety issue: No ]
    PK Population.

  • Terminal Half-Life (t1/2) of Digoxin [ Time Frame: 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 ] [ Designated as safety issue: No ]
    PK Population.

  • Apparent Clearance (CL/F) of Digoxin [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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. PK Population.


Enrollment: 29
Study Start Date: July 2013
Study Completion Date: June 2014
Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Vemurafenib + 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.
Drug: Digoxin
Participants received single oral dose of digoxin 0.25 mg tablet on Day 1 and Day 29.
Drug: Vemurafenib
Participants received vemurafenib 960 mg tablet orally BID from Day 8 to Day 35.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01765569

Locations
Belarus
Minsk, Belarus, BU-220013
Minsk District, Belarus, 223040
Vitebsk, Belarus, BU-210603
Israel
Haifa, Israel, 31096
Tel Aviv, Israel, 6423906
Tel Hashomer, Israel, 52661
Korea, Republic of
Daegu, Korea, Republic of, 702-911
Seoul, Korea, Republic of, 135-710
Seoul, Korea, Republic of, 110-774
Russian Federation
Kazan, Russian Federation, 420029
Moscow, Russian Federation, 115478
St. Petersburg, Russian Federation, 197758
South Africa
Johannesburg, South Africa, 2193
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

No publications provided

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01765569     History of Changes
Other Study ID Numbers: GO28394, 2012-003459-13
Study First Received: January 9, 2013
Results First Received: July 14, 2015
Last Updated: July 14, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Melanoma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Neuroendocrine Tumors
Nevi and Melanomas
Digoxin
Anti-Arrhythmia Agents
Cardiotonic Agents
Cardiovascular Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 03, 2015