Trial Outcomes & Findings for A Pharmacokinetics Study to Investigate the Effect of Vemurafenib on Digoxin in Patients With BRAFV600 Mutation-Positive Metastatic Melanoma (NCT NCT01765569)
NCT ID: NCT01765569
Last Updated: 2015-09-23
Results Overview
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.
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
29 participants
Primary outcome timeframe
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
Results posted on
2015-09-23
Participant Flow
Participant milestones
| Measure |
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.
|
|---|---|
|
Period A
STARTED
|
29
|
|
Period A
COMPLETED
|
29
|
|
Period A
NOT COMPLETED
|
0
|
|
Period B
STARTED
|
29
|
|
Period B
COMPLETED
|
28
|
|
Period B
NOT COMPLETED
|
1
|
|
Period C
STARTED
|
28
|
|
Period C
COMPLETED
|
27
|
|
Period C
NOT COMPLETED
|
1
|
Reasons for withdrawal
| Measure |
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.
|
|---|---|
|
Period B
Withdrawal by Subject
|
1
|
|
Period C
Death
|
1
|
Baseline Characteristics
A Pharmacokinetics Study to Investigate the Effect of Vemurafenib on Digoxin in Patients With BRAFV600 Mutation-Positive Metastatic Melanoma
Baseline characteristics by cohort
| Measure |
Vemurafenib + Digoxin
n=29 Participants
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.
|
|---|---|
|
Age, Continuous
|
47.8 years
STANDARD_DEVIATION 13.7 • n=5 Participants
|
|
Sex: Female, Male
Female
|
16 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
13 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 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 dosePopulation: PK Population included participants for whom PK data were collected.
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.
Outcome measures
| Measure |
Period A (Digoxin)
n=26 Participants
Participants received single oral dose of digoxin 0.25 mg tablet on Day 1.
|
Period C (Digoxin + Vemurafenib)
n=26 Participants
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.
|
|---|---|---|
|
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUClast) of Digoxin
|
14.9 hour*ng/mL
Standard Deviation 4.22
|
27.7 hour*ng/mL
Standard Deviation 10.6
|
PRIMARY outcome
Timeframe: 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 dosePopulation: PK Population. Number of participants analysed = participants evaluable for the analysis.
Outcome measures
| Measure |
Period A (Digoxin)
n=11 Participants
Participants received single oral dose of digoxin 0.25 mg tablet on Day 1.
|
Period C (Digoxin + Vemurafenib)
n=11 Participants
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.
|
|---|---|---|
|
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Digoxin
|
18.5 hour*ng/mL
Standard Deviation 4.64
|
35.4 hour*ng/mL
Standard Deviation 4.16
|
PRIMARY outcome
Timeframe: 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 dosePopulation: PK Population.
Outcome measures
| Measure |
Period A (Digoxin)
n=26 Participants
Participants received single oral dose of digoxin 0.25 mg tablet on Day 1.
|
Period C (Digoxin + Vemurafenib)
n=26 Participants
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.
|
|---|---|---|
|
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC24) of Digoxin
|
7.73 hour*ng/mL
Standard Deviation 1.86
|
10.6 hour*ng/mL
Standard Deviation 2.9
|
PRIMARY outcome
Timeframe: 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 dosePopulation: PK Population.
Outcome measures
| Measure |
Period A (Digoxin)
n=26 Participants
Participants received single oral dose of digoxin 0.25 mg tablet on Day 1.
|
Period C (Digoxin + Vemurafenib)
n=26 Participants
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.
|
|---|---|---|
|
Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC168) of Digoxin
|
18.2 hour*ng/mL
Standard Deviation 4.85
|
29.7 hour*ng/mL
Standard Deviation 9.62
|
PRIMARY outcome
Timeframe: 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 dosePopulation: PK Population.
Outcome measures
| Measure |
Period A (Digoxin)
n=26 Participants
Participants received single oral dose of digoxin 0.25 mg tablet on Day 1.
|
Period C (Digoxin + Vemurafenib)
n=26 Participants
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.
|
|---|---|---|
|
Maximum Plasma Concentration (Cmax) of Digoxin
|
1.36 ng/mL
Standard Deviation 0.408
|
1.99 ng/mL
Standard Deviation 0.562
|
PRIMARY outcome
Timeframe: 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 dosePopulation: PK Population.
Outcome measures
| Measure |
Period A (Digoxin)
n=26 Participants
Participants received single oral dose of digoxin 0.25 mg tablet on Day 1.
|
Period C (Digoxin + Vemurafenib)
n=26 Participants
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.
|
|---|---|---|
|
Time to Maximum Plasma Concentration (Tmax) of Digoxin
|
1 hours
Interval 0.5 to 3.0
|
1 hours
Interval 0.47 to 2.0
|
PRIMARY outcome
Timeframe: 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 dosePopulation: PK Population. Number of participants analysed = participants evaluable for the analysis.
Outcome measures
| Measure |
Period A (Digoxin)
n=11 Participants
Participants received single oral dose of digoxin 0.25 mg tablet on Day 1.
|
Period C (Digoxin + Vemurafenib)
n=11 Participants
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.
|
|---|---|---|
|
Terminal Half-Life (t1/2) of Digoxin
|
35 hours
Standard Deviation 8.67
|
56.4 hours
Standard Deviation 11
|
PRIMARY outcome
Timeframe: 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 dosePopulation: PK Population. Number of participants analysed = participants evaluable for the analysis.
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.
Outcome measures
| Measure |
Period A (Digoxin)
n=11 Participants
Participants received single oral dose of digoxin 0.25 mg tablet on Day 1.
|
Period C (Digoxin + Vemurafenib)
n=11 Participants
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.
|
|---|---|---|
|
Apparent Clearance (CL/F) of Digoxin
|
14.5 liters/hour
Standard Deviation 4.95
|
7.15 liters/hour
Standard Deviation 0.808
|
Adverse Events
Period A
Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths
Period B
Serious events: 2 serious events
Other events: 20 other events
Deaths: 0 deaths
Period C
Serious events: 1 serious events
Other events: 11 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Period A
n=29 participants at risk
Single oral dose of digoxin 0.25 mg tablet on Day 1.
|
Period B
n=29 participants at risk
Vemurafenib 960 mg orally BID from Day 8 to Day 28.
|
Period C
n=28 participants at risk
Single oral dose of digoxin 0.25 mg on Day 29, and vemurafenib 960 mg orally BID from Day 29 to Day 35.
|
|---|---|---|---|
|
Blood and lymphatic system disorders
Neutropenia
|
0.00%
0/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
0.00%
0/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
3.6%
1/28 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
|
Skin and subcutaneous tissue disorders
Rash
|
0.00%
0/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
3.4%
1/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
0.00%
0/28 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
|
Infections and infestations
Upper respiratory tract infection
|
0.00%
0/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
3.4%
1/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
0.00%
0/28 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
Other adverse events
| Measure |
Period A
n=29 participants at risk
Single oral dose of digoxin 0.25 mg tablet on Day 1.
|
Period B
n=29 participants at risk
Vemurafenib 960 mg orally BID from Day 8 to Day 28.
|
Period C
n=28 participants at risk
Single oral dose of digoxin 0.25 mg on Day 29, and vemurafenib 960 mg orally BID from Day 29 to Day 35.
|
|---|---|---|---|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
|
0.00%
0/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
6.9%
2/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
0.00%
0/28 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
|
General disorders
Pyrexia
|
0.00%
0/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
3.4%
1/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
7.1%
2/28 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
|
General disorders
Asthenia
|
0.00%
0/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
3.4%
1/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
14.3%
4/28 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
|
General disorders
Fatigue
|
0.00%
0/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
6.9%
2/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
0.00%
0/28 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
|
Gastrointestinal disorders
Nausea
|
0.00%
0/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
10.3%
3/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
0.00%
0/28 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
|
Skin and subcutaneous tissue disorders
Rash
|
0.00%
0/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
24.1%
7/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
10.7%
3/28 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
|
Skin and subcutaneous tissue disorders
Rash maculo-papular
|
0.00%
0/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
10.3%
3/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
0.00%
0/28 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
|
Skin and subcutaneous tissue disorders
Alopecia
|
0.00%
0/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
0.00%
0/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
7.1%
2/28 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
|
Skin and subcutaneous tissue disorders
Hyperkeratosis
|
0.00%
0/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
0.00%
0/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
7.1%
2/28 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
|
Musculoskeletal and connective tissue disorders
Myalgia
|
0.00%
0/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
13.8%
4/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
0.00%
0/28 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
|
Musculoskeletal and connective tissue disorders
Arthralgia
|
0.00%
0/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
17.2%
5/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
7.1%
2/28 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
|
Metabolism and nutrition disorders
Decreased appetite
|
0.00%
0/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
6.9%
2/29 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
3.6%
1/28 • From Screening to 28 days after the last dose of study treatment or until initiation of another anticancer therapy, whichever occurred first.
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee The study being conducted under this agreement is part of the overall study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the study, but after the first publication or presentation that involves the overall study. Sponsor may request that confidential information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
- Publication restrictions are in place
Restriction type: OTHER