Malignant Melanoma
Conditions
Brief summary
This open-label study will assess the pharmacokinetics, efficacy and safety of RO5185426 administered as 240mg tablets in previously treated patients with metastatic melanoma. Patients will be randomized to receive one of four dose-levels of RO5185426 \[RG7204; PLEXXIKON; PLX4032\] orally twice daily on days 1 to 15 (morning dose). Starting on day 22, treatment with RO5185426 may be resumed at a dose of 960 mg twice daily and continued until disease progression. Target sample size is \<100 patients.
Interventions
DRUGRO5185426
dosage b) orally twice daily, days 1-15 (morning dose)
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* adult patients, \>/=18 years of age * histologically confirmed metastatic melanoma, stage IIIc or IV (AJCC) * failure of at least one prior standard of care regimen * positive for BRAF V600E mutation (by Roche CoDx BRAF mutation assay) * ECOG performance status 0 or 1 * adequate hematologic, renal and liver function
Exclusion criteria
* active CNS lesions on CT/MRI within 28 days prior to enrollment * history of spinal cord compression o carcinomatous meningitis * anticipated or ongoing anti-cancer therapies other than those administered in this study * previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor * severe cardiovascular disease within 6 months prior to study * previous malignancy within the past 5 years except for basal or squamous cell carcinoma of the skin, melanoma in-situ and carcinoma in-situ of the cervix
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Accumulation Ratio of Vemurafenib on Day 15 | Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 and 15 | Accumulation ratio was calculated as, AUC(0-8) on Day 15 divided by AUC(0-8) on Day 1. |
| Apparent Clearance (CL/F) of Vemurafenib on Day 15 | Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15 | 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. |
| Terminal Elimination Half-Life (t1/2) of Vemurafenib on Day 15 | Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15 | Time measured for vemurafenib plasma concentrations to decrease by one-half (t1/2) was calculated as 0.693 divided by apparent first-order terminal elimination rate constant (0.693/kel). |
| Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 15 | Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15 | — |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 1 | Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 | — |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 1 | Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 1 | — |
| Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 1 | Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 | — |
| Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 1 | Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 | — |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 9 | Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9 | — |
| Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 9 | Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9 | — |
| Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 9 | Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9 | — |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 15 | Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 15 | — |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 15 | Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 15 | — |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC[0-168h]) of Vemurafenib on Day 15 | Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15 | — |
| Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15 | Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to approximately 3 years (assessed at Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, thereafter every 2 cycles and then every 4 cycles after Cycle 13) | OS was defined as the time, in months, from the date of the first study drug administration to the date of death, regardless of the cause of death. |
| Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) | Up to approximately 3 years (assessed at Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, thereafter every 2 cycles and then every 4 cycles after Cycle 13) | Confirmed best overall response was defined as having best objective response as CR or PR, as assessed by investigator and confirmed at least 28 days after initial response. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1). CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) were required to demonstrate a reduction to normal (short axis less than \[\<\] 10 millimeters \[mm\]). PR was defined as a 30 percent (%) decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter. Percentage of participants with best overall response of confirmed CR or PR are reported. |
Countries
Australia, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 - Vemurafenib 240 mg Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal. | 12 |
| Cohort 2 - Vemurafenib 480 mg Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal. | 12 |
| Cohort 3 - Vemurafenib 720 mg Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal. | 12 |
| Cohort 4 - Vemurafenib 960 mg Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal. | 16 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Disease Progression | 45 |
| Overall Study | Entered Extension Study | 1 |
| Overall Study | Started Other Therapy | 1 |
| Overall Study | Study Closing | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Cohort 1 - Vemurafenib 240 mg | Cohort 2 - Vemurafenib 480 mg | Cohort 3 - Vemurafenib 720 mg | Cohort 4 - Vemurafenib 960 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 52.0 years STANDARD_DEVIATION 15.06 | 46.3 years STANDARD_DEVIATION 10.58 | 54.3 years STANDARD_DEVIATION 10.7 | 50.5 years STANDARD_DEVIATION 11.91 | 50.8 years STANDARD_DEVIATION 12.14 |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 6 Participants | 8 Participants | 26 Participants |
| Sex: Female, Male Male | 7 Participants | 5 Participants | 6 Participants | 8 Participants | 26 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 | 12 / 12 | 12 / 12 | 12 / 12 | 16 / 16 |
| serious Total, serious adverse events | 3 / 12 | 3 / 12 | 8 / 12 | 7 / 16 |
Outcome results
Primary
Accumulation Ratio of Vemurafenib on Day 15
Accumulation ratio was calculated as, AUC(0-8) on Day 15 divided by AUC(0-8) on Day 1.
Time frame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 and 15
Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Vemurafenib 240 mg | Accumulation Ratio of Vemurafenib on Day 15 | 24.9 ratio | Standard Deviation 29.4 |
| Cohort 2 - Vemurafenib 480 mg | Accumulation Ratio of Vemurafenib on Day 15 | 23.3 ratio | Standard Deviation 16 |
| Cohort 3 - Vemurafenib 720 mg | Accumulation Ratio of Vemurafenib on Day 15 | 18.8 ratio | Standard Deviation 12.4 |
| Cohort 4 - Vemurafenib 960 mg | Accumulation Ratio of Vemurafenib on Day 15 | 23.2 ratio | Standard Deviation 16.5 |
Primary
Apparent Clearance (CL/F) of Vemurafenib on Day 15
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.
Time frame: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15
Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Vemurafenib 240 mg | Apparent Clearance (CL/F) of Vemurafenib on Day 15 | 0.3 liters/hour (L/h) | Standard Deviation 0.13 |
| Cohort 2 - Vemurafenib 480 mg | Apparent Clearance (CL/F) of Vemurafenib on Day 15 | 0.8 liters/hour (L/h) | Standard Deviation 1.45 |
| Cohort 3 - Vemurafenib 720 mg | Apparent Clearance (CL/F) of Vemurafenib on Day 15 | 0.4 liters/hour (L/h) | Standard Deviation 0.28 |
| Cohort 4 - Vemurafenib 960 mg | Apparent Clearance (CL/F) of Vemurafenib on Day 15 | 0.3 liters/hour (L/h) | Standard Deviation 0.19 |
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC[0-168h]) of Vemurafenib on Day 15
Time frame: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15
Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Vemurafenib 240 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC[0-168h]) of Vemurafenib on Day 15 | 920.3 mcg*h/mL | Standard Deviation 538.35 |
| Cohort 2 - Vemurafenib 480 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC[0-168h]) of Vemurafenib on Day 15 | 2243.5 mcg*h/mL | Standard Deviation 1336.15 |
| Cohort 3 - Vemurafenib 720 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC[0-168h]) of Vemurafenib on Day 15 | 3127.1 mcg*h/mL | Standard Deviation 1789.97 |
| Cohort 4 - Vemurafenib 960 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC[0-168h]) of Vemurafenib on Day 15 | 3530.3 mcg*h/mL | Standard Deviation 1811.43 |
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 1
Time frame: Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 1
Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Vemurafenib 240 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 1 | 40.9 mcg*h/mL | Standard Deviation 23.43 |
| Cohort 2 - Vemurafenib 480 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 1 | 62.4 mcg*h/mL | Standard Deviation 35.71 |
| Cohort 3 - Vemurafenib 720 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 1 | 111.6 mcg*h/mL | Standard Deviation 34.22 |
| Cohort 4 - Vemurafenib 960 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 1 | 130.6 mcg*h/mL | Standard Deviation 71.78 |
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 15
Time frame: Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 15
Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Vemurafenib 240 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 15 | 317.7 mcg*h/mL | Standard Deviation 133.34 |
| Cohort 2 - Vemurafenib 480 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 15 | 598.8 mcg*h/mL | Standard Deviation 297.44 |
| Cohort 3 - Vemurafenib 720 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 15 | 1003.7 mcg*h/mL | Standard Deviation 441.36 |
| Cohort 4 - Vemurafenib 960 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 15 | 1126.0 mcg*h/mL | Standard Deviation 423.01 |
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 1
Time frame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1
Population: Pharmacokinetic (PK) population included all participants who provided essential PK data up to and including the pre-dose PK sample taken on Cycle 1, Day 22, without major protocol violation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Vemurafenib 240 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 1 | 8.3 micrograms*hour/milliliter (mcg*h/mL) | Standard Deviation 6.13 |
| Cohort 2 - Vemurafenib 480 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 1 | 13.8 micrograms*hour/milliliter (mcg*h/mL) | Standard Deviation 7.72 |
| Cohort 3 - Vemurafenib 720 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 1 | 21.9 micrograms*hour/milliliter (mcg*h/mL) | Standard Deviation 12.97 |
| Cohort 4 - Vemurafenib 960 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 1 | 27.0 micrograms*hour/milliliter (mcg*h/mL) | Standard Deviation 18.87 |
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 15
Time frame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 15
Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Vemurafenib 240 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 15 | 117.8 mcg*h/mL | Standard Deviation 50.52 |
| Cohort 2 - Vemurafenib 480 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 15 | 233.8 mcg*h/mL | Standard Deviation 106.93 |
| Cohort 3 - Vemurafenib 720 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 15 | 343.3 mcg*h/mL | Standard Deviation 151.23 |
| Cohort 4 - Vemurafenib 960 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 15 | 392.2 mcg*h/mL | Standard Deviation 126.37 |
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 9
Time frame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9
Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Vemurafenib 240 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 9 | 102.1 mcg*h/mL | Standard Deviation 41.37 |
| Cohort 2 - Vemurafenib 480 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 9 | 180.0 mcg*h/mL | Standard Deviation 84.23 |
| Cohort 3 - Vemurafenib 720 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 9 | 301.2 mcg*h/mL | Standard Deviation 108.67 |
| Cohort 4 - Vemurafenib 960 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 9 | 329.0 mcg*h/mL | Standard Deviation 108.85 |
Primary
Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 1
Time frame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1
Population: PK population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Vemurafenib 240 mg | Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 1 | 1.9 micrograms/milliliter (mcg/mL) | Standard Deviation 1.66 |
| Cohort 2 - Vemurafenib 480 mg | Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 1 | 2.6 micrograms/milliliter (mcg/mL) | Standard Deviation 1.56 |
| Cohort 3 - Vemurafenib 720 mg | Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 1 | 4.4 micrograms/milliliter (mcg/mL) | Standard Deviation 1.98 |
| Cohort 4 - Vemurafenib 960 mg | Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 1 | 4.8 micrograms/milliliter (mcg/mL) | Standard Deviation 3.34 |
Primary
Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15
Time frame: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15
Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Vemurafenib 240 mg | Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15 | 17.2 mcg/mL | Standard Deviation 7.43 |
| Cohort 2 - Vemurafenib 480 mg | Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15 | 35.4 mcg/mL | Standard Deviation 17.44 |
| Cohort 3 - Vemurafenib 720 mg | Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15 | 52.7 mcg/mL | Standard Deviation 22.4 |
| Cohort 4 - Vemurafenib 960 mg | Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15 | 61.4 mcg/mL | Standard Deviation 22.76 |
Primary
Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 9
Time frame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9
Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Vemurafenib 240 mg | Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 9 | 15.4 mcg/mL | Standard Deviation 5.84 |
| Cohort 2 - Vemurafenib 480 mg | Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 9 | 28.9 mcg/mL | Standard Deviation 16.95 |
| Cohort 3 - Vemurafenib 720 mg | Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 9 | 45.9 mcg/mL | Standard Deviation 14.44 |
| Cohort 4 - Vemurafenib 960 mg | Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 9 | 53.2 mcg/mL | Standard Deviation 19.08 |
Primary
Terminal Elimination Half-Life (t1/2) of Vemurafenib on Day 15
Time measured for vemurafenib plasma concentrations to decrease by one-half (t1/2) was calculated as 0.693 divided by apparent first-order terminal elimination rate constant (0.693/kel).
Time frame: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15
Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Vemurafenib 240 mg | Terminal Elimination Half-Life (t1/2) of Vemurafenib on Day 15 | 31.5 hours | Standard Deviation 19.05 |
| Cohort 2 - Vemurafenib 480 mg | Terminal Elimination Half-Life (t1/2) of Vemurafenib on Day 15 | 38.4 hours | Standard Deviation 24.18 |
| Cohort 3 - Vemurafenib 720 mg | Terminal Elimination Half-Life (t1/2) of Vemurafenib on Day 15 | 34.9 hours | Standard Deviation 19.48 |
| Cohort 4 - Vemurafenib 960 mg | Terminal Elimination Half-Life (t1/2) of Vemurafenib on Day 15 | 34.1 hours | Standard Deviation 19.66 |
Primary
Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 1
Time frame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1
Population: PK population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - Vemurafenib 240 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 1 | 4.0 hours |
| Cohort 2 - Vemurafenib 480 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 1 | 4.0 hours |
| Cohort 3 - Vemurafenib 720 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 1 | 5.0 hours |
| Cohort 4 - Vemurafenib 960 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 1 | 5.0 hours |
Primary
Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 15
Time frame: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15
Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - Vemurafenib 240 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 15 | 4.0 hours |
| Cohort 2 - Vemurafenib 480 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 15 | 2.3 hours |
| Cohort 3 - Vemurafenib 720 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 15 | 2.0 hours |
| Cohort 4 - Vemurafenib 960 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 15 | 2.0 hours |
Primary
Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 9
Time frame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9
Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - Vemurafenib 240 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 9 | 2.0 hours |
| Cohort 2 - Vemurafenib 480 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 9 | 2.0 hours |
| Cohort 3 - Vemurafenib 720 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 9 | 0.0 hours |
| Cohort 4 - Vemurafenib 960 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 9 | 1.8 hours |
Secondary
Overall Survival (OS)
OS was defined as the time, in months, from the date of the first study drug administration to the date of death, regardless of the cause of death.
Time frame: Up to approximately 3 years (assessed at Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, thereafter every 2 cycles and then every 4 cycles after Cycle 13)
Population: Data for this outcome measure was not collected as the outcome was removed as per changes in planned analysis (protocol amendment).
Secondary
Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR)
Confirmed best overall response was defined as having best objective response as CR or PR, as assessed by investigator and confirmed at least 28 days after initial response. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1). CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) were required to demonstrate a reduction to normal (short axis less than \[\<\] 10 millimeters \[mm\]). PR was defined as a 30 percent (%) decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter. Percentage of participants with best overall response of confirmed CR or PR are reported.
Time frame: Up to approximately 3 years (assessed at Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, thereafter every 2 cycles and then every 4 cycles after Cycle 13)
Population: Efficacy population: all enrolled participants who received at least one dose of vemurafenib, had measurable target lesions at baseline based on RECIST 1.1 criteria, had no major protocol violations of inclusion/exclusion criteria, and had no other violations affecting efficacy assessments.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Vemurafenib 240 mg | Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) | 49 percentage of participants |