Malignant Melanoma, Neoplasms
Conditions
Brief summary
This open-label, multi-center, three-period, one-sequence study will investigate the effect of rifampin on the PK of vemurafenib in participants 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. Eligible participants will have the option to continue treatment with vemurafenib as part of an extension study GO28399 (NCT01739764).
Interventions
DRUGRifampin
Rifampin at a dose of 600 mg as capsules orally once daily will be administered from Days 8 through 23 (Periods B and C).
DRUGVemurafenib
Participants, after an overnight fast of at least 10 hours, will receive vemurafenib at a dose of 960 mg as film-coated tablets orally on Day 1 (Period A) and on Day 17 (Period C).
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with either unresectable Stage IIIc or Stage IV metastatic melanoma positive for the BRAF V600 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 Deoxyribonucleic acid (DNA) sequencing method, and who have no acceptable standard treatment options * Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 * Life expectancy of greater than or equal to (\>/=) 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 participants of childbearing potential and male participants with partners of childbearing potential must agree to always use 2 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 * Requirement for immediate or urgent treatment with daily vemurafenib and for whom the intermittent schedule of vemurafenib employed during the 24-day period for this trial is not clinically acceptable * Allergy or hypersensitivity to components of the vemurafenib formulation * Experimental therapy within 4 weeks prior to first dose of study drug * Major surgical procedure or significant traumatic injury within 14 days prior to first dose of study drug, or anticipation of the need for major surgery during study treatment * 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 corrected QT interval (QTc) greater than (\>) 450 milliseconds * Active central nervous system lesions * Uncontrolled or poorly controlled diabetes * Current severe, uncontrolled systemic disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Vemurafenib | Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C) | Cmax is the maximum observed plasma vemurafenib concentration, presented in microgram per milliliter (mcg/mL). |
| Area Under the Plasma Concentration Time-curve From Zero to the Last Measurable Concentration Time Point (AUClast) of Vemurafenib | Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C) | AUClast is the area under the vemurafenib plasma concentration versus time curve from time zero to the time of last measured concentration of vemurafenib (Tlast). Area under the curve (AUC) is a measure of the plasma concentration of a drug over time. AUClast is presented in micrograms times (\*) hour per milliliter (mcg\*h/mL). |
| Area Under the Plasma Concentration Time-curve From Zero to Extrapolated Infinite Time (AUC[0-inf]) of Vemurafenib | Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C) | AUC(0-inf) is the AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of a drug over time. AUC(0-inf) is presented in mcg\*h/mL. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Time-curve From Zero to 168 Hours [AUC(0-168)] of Vemurafenib | Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C) | AUC(0-168) is the AUC from time zero (pre-dose) to 168 hours (time point for last blood sample collection). AUC is a measure of the plasma concentration of a drug over time. AUC(0-168) is presented in mcg\*h/mL. |
| Time to Reach Cmax (Tmax) of Vemurafenib | Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C) | Tmax is the time from vemurafenib administration to reach Cmax for vemurafenib. |
| Percent Extrapolated AUC(0-inf) (AUCpeo) of Vemurafenib | Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C) | The AUCpeo, that is, percent area obtained after extrapolation from Tlast to infinity is calculated by using the formula AUCpeo = 100\*(AUC\[0-inf\] minus AUC\[0-last\])/AUC(0-inf). This parameter provides information about what percentage of the theoretical curve AUC(0-inf) is possible to determine experimentally (AUC0-last). |
| Plasma Elimination Half Life (t1/2) of Vemurafenib | Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C) | Plasma elimination half-life is the time measured during drug elimination phase for the plasma drug concentration to decrease by one half. |
| Plasma Apparent Clearance (CL/F) of Vemurafenib | Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C) | Clearance of a drug is a measure of the rate at which a drug is removed (metabolized or eliminated by normal biological processes) from the blood. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. |
Countries
Brazil, Croatia, Egypt, South Africa, United States
Participant flow
Pre-assignment details
A total of 27 participants were enrolled into the study.
Participants by arm
| Arm | Count |
|---|---|
| Vemurafenib + Rifampin (All Periods) There were 3 intervention periods in the study: Period A (Days 1 to 7), Period B (Days 8 to 16), and Period C (Days 17 to 24). Participants, after an overnight fast of at least 10 hours, received vemurafenib at a dose of 960 mg as film-coated tablets orally alone on Day 1 (Period A); with rifampin (at a dose of 600 mg as capsules orally) on Day 17 (Period C); and rifampin alone at a dose of 600 mg as capsules orally once daily was administered from Days 8 through 16 (Period B) and from Days 18 through 23 (Period C). | 27 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Vemurafenib + Rifampin (All Periods) |
|---|---|
| Age, Continuous | 57.9 years STANDARD_DEVIATION 13 |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 27 | 8 / 26 | 5 / 25 | 12 / 27 |
| serious Total, serious adverse events | 0 / 27 | 0 / 26 | 2 / 25 | 2 / 27 |
Outcome results
Primary
Area Under the Plasma Concentration Time-curve From Zero to Extrapolated Infinite Time (AUC[0-inf]) of Vemurafenib
AUC(0-inf) is the AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of a drug over time. AUC(0-inf) is presented in mcg\*h/mL.
Time frame: Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)
Population: PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Vemurafenib (Intervention Period A) | Area Under the Plasma Concentration Time-curve From Zero to Extrapolated Infinite Time (AUC[0-inf]) of Vemurafenib | 131 mcg*h/mL | Geometric Coefficient of Variation 104.2 |
| Vemurafenib + Rifampin (Intervention Period C) | Area Under the Plasma Concentration Time-curve From Zero to Extrapolated Infinite Time (AUC[0-inf]) of Vemurafenib | 78.1 mcg*h/mL | Geometric Coefficient of Variation 74.3 |
Comparison: ANOVA was applied to the log-transformed PK parameters, and then back transformed to provide geometric mean ratio (Period C/Period A) and confidence intervals.90% CI: [0.469, 0.759]
Primary
Area Under the Plasma Concentration Time-curve From Zero to the Last Measurable Concentration Time Point (AUClast) of Vemurafenib
AUClast is the area under the vemurafenib plasma concentration versus time curve from time zero to the time of last measured concentration of vemurafenib (Tlast). Area under the curve (AUC) is a measure of the plasma concentration of a drug over time. AUClast is presented in micrograms times (\*) hour per milliliter (mcg\*h/mL).
Time frame: Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)
Population: The pharmacokinetics (PK) parameter population included all participants who received both scheduled doses of vemurafenib and who provided adequate PK assessments to calculate important PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Vemurafenib (Intervention Period A) | Area Under the Plasma Concentration Time-curve From Zero to the Last Measurable Concentration Time Point (AUClast) of Vemurafenib | 125 mcg*h/mL | Geometric Coefficient of Variation 101.4 |
| Vemurafenib + Rifampin (Intervention Period C) | Area Under the Plasma Concentration Time-curve From Zero to the Last Measurable Concentration Time Point (AUClast) of Vemurafenib | 76.7 mcg*h/mL | Geometric Coefficient of Variation 75.3 |
Comparison: Analysis of variance (ANOVA) was applied to the log-transformed PK parameters, and then back transformed to provide geometric mean ratio (Period C/Period A) and confidence intervals.90% CI: [0.484, 0.78]
Primary
Maximum Observed Plasma Concentration (Cmax) of Vemurafenib
Cmax is the maximum observed plasma vemurafenib concentration, presented in microgram per milliliter (mcg/mL).
Time frame: Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)
Population: PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Vemurafenib (Intervention Period A) | Maximum Observed Plasma Concentration (Cmax) of Vemurafenib | 4.45 mcg/mL | Geometric Coefficient of Variation 63.3 |
| Vemurafenib + Rifampin (Intervention Period C) | Maximum Observed Plasma Concentration (Cmax) of Vemurafenib | 4.95 mcg/mL | Geometric Coefficient of Variation 59.1 |
Comparison: ANOVA was applied to the log-transformed PK parameters, and then back transformed to provide geometric mean ratio (Period C/Period A) and confidence intervals.90% CI: [0.908, 1.36]
Other Pre-specified
Area Under the Plasma Concentration Time-curve From Zero to 168 Hours [AUC(0-168)] of Vemurafenib
AUC(0-168) is the AUC from time zero (pre-dose) to 168 hours (time point for last blood sample collection). AUC is a measure of the plasma concentration of a drug over time. AUC(0-168) is presented in mcg\*h/mL.
Time frame: Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)
Population: PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Vemurafenib (Intervention Period A) | Area Under the Plasma Concentration Time-curve From Zero to 168 Hours [AUC(0-168)] of Vemurafenib | 126 mcg*h/mL | Geometric Coefficient of Variation 99.6 |
| Vemurafenib + Rifampin (Intervention Period C) | Area Under the Plasma Concentration Time-curve From Zero to 168 Hours [AUC(0-168)] of Vemurafenib | 78.0 mcg*h/mL | Geometric Coefficient of Variation 74.2 |
Other Pre-specified
Percent Extrapolated AUC(0-inf) (AUCpeo) of Vemurafenib
The AUCpeo, that is, percent area obtained after extrapolation from Tlast to infinity is calculated by using the formula AUCpeo = 100\*(AUC\[0-inf\] minus AUC\[0-last\])/AUC(0-inf). This parameter provides information about what percentage of the theoretical curve AUC(0-inf) is possible to determine experimentally (AUC0-last).
Time frame: Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)
Population: PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Vemurafenib (Intervention Period A) | Percent Extrapolated AUC(0-inf) (AUCpeo) of Vemurafenib | 2.75 percent AUC | Geometric Coefficient of Variation 150.4 |
| Vemurafenib + Rifampin (Intervention Period C) | Percent Extrapolated AUC(0-inf) (AUCpeo) of Vemurafenib | 1.26 percent AUC | Geometric Coefficient of Variation 95.9 |
Other Pre-specified
Plasma Apparent Clearance (CL/F) of Vemurafenib
Clearance of a drug is a measure of the rate at which a drug is removed (metabolized or eliminated by normal biological processes) from the blood. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.
Time frame: Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)
Population: PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Vemurafenib (Intervention Period A) | Plasma Apparent Clearance (CL/F) of Vemurafenib | 7.35 liters/hour | Geometric Coefficient of Variation 104.2 |
| Vemurafenib + Rifampin (Intervention Period C) | Plasma Apparent Clearance (CL/F) of Vemurafenib | 12.3 liters/hour | Geometric Coefficient of Variation 74.3 |
Other Pre-specified
Plasma Elimination Half Life (t1/2) of Vemurafenib
Plasma elimination half-life is the time measured during drug elimination phase for the plasma drug concentration to decrease by one half.
Time frame: Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)
Population: PK parameter population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vemurafenib (Intervention Period A) | Plasma Elimination Half Life (t1/2) of Vemurafenib | 29.7 hours | Standard Deviation 17.6 |
| Vemurafenib + Rifampin (Intervention Period C) | Plasma Elimination Half Life (t1/2) of Vemurafenib | 11.6 hours | Standard Deviation 5.24 |
Other Pre-specified
Time to Reach Cmax (Tmax) of Vemurafenib
Tmax is the time from vemurafenib administration to reach Cmax for vemurafenib.
Time frame: Predose (0 hour), 1, 2, 4, 6, 8, 12, 24, 30-32, 48, 72, 96, 120, 168 hours post vemurafenib-dose on Day 1 (Period A) and Day 17 (Period C)
Population: PK parameter population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vemurafenib (Intervention Period A) | Time to Reach Cmax (Tmax) of Vemurafenib | 4.00 hours |
| Vemurafenib + Rifampin (Intervention Period C) | Time to Reach Cmax (Tmax) of Vemurafenib | 4.00 hours |