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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

Status
Completed
Phases
Phase 1
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT01765569
Enrollment
29
Registered
2013-01-10
Start date
2013-07-31
Completion date
2014-06-30
Last updated
2015-09-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Malignant Melanoma, Neoplasms

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.

Interventions

DRUGDigoxin

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

DRUGVemurafenib

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

Sponsors

Hoffmann-La Roche
Lead SponsorINDUSTRY

Study design

Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No

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

Design outcomes

Primary

MeasureTime frameDescription
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUClast) of DigoxinHour [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 doseAUClast = 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.
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of DigoxinHour [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 24 Hours (AUC24) of DigoxinHour [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 DigoxinHour [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—
Maximum Plasma Concentration (Cmax) of DigoxinHour [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—
Time to Maximum Plasma Concentration (Tmax) of DigoxinHour [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 DigoxinHour [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 DigoxinHour [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 doseClearance 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.

Countries

Belarus, Israel, Russia, South Africa, South Korea

Participant flow

Participants by arm

ArmCount
Vemurafenib + Digoxin
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.
29
Total29

Withdrawals & dropouts

PeriodReasonFG000
Period BWithdrawal by Subject1
Period CDeath1

Baseline characteristics

CharacteristicVemurafenib + Digoxin
Age, Continuous47.8 years
STANDARD_DEVIATION 13.7
Sex: Female, Male
Female
16 Participants
Sex: Female, Male
Male
13 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
deaths
Total, all-cause mortality
— / —— / —— / —
other
Total, other adverse events
0 / 2920 / 2911 / 28
serious
Total, serious adverse events
0 / 292 / 291 / 28

Outcome results

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.

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

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

ArmMeasureValue (MEAN)Dispersion
Period A (Digoxin)Apparent Clearance (CL/F) of Digoxin14.5 liters/hourStandard Deviation 4.95
Period C (Digoxin + Vemurafenib)Apparent Clearance (CL/F) of Digoxin7.15 liters/hourStandard Deviation 0.808
Primary

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

Population: PK Population.

ArmMeasureValue (MEAN)Dispersion
Period A (Digoxin)Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC168) of Digoxin18.2 hour*ng/mLStandard Deviation 4.85
Period C (Digoxin + Vemurafenib)Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC168) of Digoxin29.7 hour*ng/mLStandard Deviation 9.62
Primary

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

Population: PK Population.

ArmMeasureValue (MEAN)Dispersion
Period A (Digoxin)Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC24) of Digoxin7.73 hour*ng/mLStandard Deviation 1.86
Period C (Digoxin + Vemurafenib)Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC24) of Digoxin10.6 hour*ng/mLStandard Deviation 2.9
Primary

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

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

ArmMeasureValue (MEAN)Dispersion
Period A (Digoxin)Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Digoxin18.5 hour*ng/mLStandard Deviation 4.64
Period C (Digoxin + Vemurafenib)Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Digoxin35.4 hour*ng/mLStandard Deviation 4.16
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.

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

Population: PK Population included participants for whom PK data were collected.

ArmMeasureValue (MEAN)Dispersion
Period A (Digoxin)Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUClast) of Digoxin14.9 hour*ng/mLStandard Deviation 4.22
Period C (Digoxin + Vemurafenib)Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUClast) of Digoxin27.7 hour*ng/mLStandard Deviation 10.6
90% CI: [1.63, 2.02]
Primary

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

Population: PK Population.

ArmMeasureValue (MEAN)Dispersion
Period A (Digoxin)Maximum Plasma Concentration (Cmax) of Digoxin1.36 ng/mLStandard Deviation 0.408
Period C (Digoxin + Vemurafenib)Maximum Plasma Concentration (Cmax) of Digoxin1.99 ng/mLStandard Deviation 0.562
90% CI: [1.3, 1.65]
Primary

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

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

ArmMeasureValue (MEAN)Dispersion
Period A (Digoxin)Terminal Half-Life (t1/2) of Digoxin35 hoursStandard Deviation 8.67
Period C (Digoxin + Vemurafenib)Terminal Half-Life (t1/2) of Digoxin56.4 hoursStandard Deviation 11
Primary

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

Population: PK Population.

ArmMeasureValue (MEDIAN)
Period A (Digoxin)Time to Maximum Plasma Concentration (Tmax) of Digoxin1 hours
Period C (Digoxin + Vemurafenib)Time to Maximum Plasma Concentration (Tmax) of Digoxin1 hours

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026