Malignant Melanoma
Conditions
Brief summary
This open-label single-arm study will evaluate the effect of RO5185426 \[RG7204; PLEXXIKON: PLX4032\] on the pharmacokinetics of five CYP450 substrates (caffeine, warfarin + vitamin K, omeprazole, dextromethorphan, midazolam) administered as a drug cocktail to patients with metastatic melanoma. The study will also evaluate efficacy and safety of RO5185426. On day 1, patients will receive the drug cocktail. On days 6 to 19, patients will receive RO5185426 twice daily. On day 20, patients will receive RO5185426 and the drug cocktail and on days 21 to 25, patients will receive RO5185426. Assessments will be made at regular intervals during the dosing periods and at follow-up. Patients may continue on study treatment (RO5185426) until the development of progressive disease or unacceptable toxicity. Target sample size \<50.
Interventions
DRUGDrug cocktail
Drug cocktail (caffeine, warfarin + vitamin K, omeprazole, dextromethorphan, midazolam) orally once daily, day 1 and day 20
DRUGRO5185426
960 mg orally twice daily
Sponsors
Hoffmann-La Roche
Study design
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patient \>/= 18 years of age * Malignant melanoma (Stage IV, AJCC) * Patients who are treatment-naive or have received prior systemic treatments for metastatic melanoma. Time elapsed between previous treatment for metastatic disease and first administration of study drug must be at least 28 days * Positive tested for BRAF mutation * Patients must not be poor metabolizers of CYP450 enzymes 2C9, 2C19, or 2D6 as determined by genotyping * Measurable disease by RECIST criteria * Negative pregnancy test; for fertile men and women, effective contraception during treatment and for 6 months after completion
Exclusion criteria
* Active CNS lesions on CT/MRI within 28 days prior to enrollment * History of known spinal cord compression, or carcinomatous meningitis * Severe cardiovascular disease within 6 months prior to study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CL/F of Probe Parent Drugs on Day 20 | Day 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours | Drug clearance was a quantitative measure of the rate at which a drug substance was removed from the body. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed. |
| Trough Plasma Concentration (Cmin) of Vemurafenib | Before morning dose (0 hour) on Day 19 | — |
| Apparent Elimination Half-Life in Plasma (t1/2) of Probe Parent Drugs and Their Metabolites on Day 1 | Day 1: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours | Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite. |
| t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 | Day 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours | Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite. |
| Apparent Plasma Clearance (CL/F) of Probe Parent Drugs on Day 1 | Day 1: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours | Drug clearance was a quantitative measure of the rate at which a drug substance was removed from the body. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed. |
| Geometric Mean Ratio of Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Observed Sampling Time (AUC[0-last]) of Probe Parent Drugs | Day 1, 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours | AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. To assess the potential for drug-drug interactions, the geometric mean ratios and corresponding 90 percent (%) confidence interval (CI) of AUC(0-last) of parent probe drug before (Day 1) and after treatment with vemurafenib (Day 20) was calculated. Ratio and corresponding 90% CI of AUC(0-last) (Day 20/Day 1) for each of the 5 probe drugs is reported. |
| Geometric Mean Ratio of Maximum Plasma Concentration (Cmax) of Probe Parent Drugs | Day 1, 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours | To assess the potential for drug-drug interactions, the geometric mean ratios and corresponding 90% CI of Cmax of parent probe drug before (Day 1) and after treatment with vemurafenib (Day 20) was calculated. Ratio and corresponding 90% CI of Cmax (Day 20/Day 1) for each of the 5 probe drugs is reported. |
| Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs | Day 1, 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for paraxanthine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120, dextrorphan 0.5, 1.5, 2, 12, 18, 48, OH-midazolam 0.08, 0.25, 0.5, 0.75, 2, 10, OH-omeprazole 0.5, 1.5, 2, 2.5, 12, 18 hours | AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. To assess the potential for drug-drug interactions, the geometric mean ratios and corresponding 90% CI of AUC(0-last) and Cmax of metabolites of parent probe drug before (Day 1) and after treatment with vemurafenib (Day 20) was calculated. Ratio and corresponding 90% CI of AUC(0-last) and Cmax (Day 20/Day 1) for each of the 4 probe drug metabolites is reported (paraxanthine \[caffeine metabolite\], dextrorphan \[dextromethorphan metabolite\], OH-midazolam \[midazolam metabolite\], OH-omeprazole (omeprazole metabolite); S-warfarin does not have a metabolite). |
| AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | Day 1: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours | AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. AUC(0-inf) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero extrapolated to infinity. Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin, as S-warfarin does not have a metabolite. |
| AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | Day 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours | AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. AUC(0-inf) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero extrapolated to infinity. Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin, as S-warfarin does not have a metabolite. |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 8, 12, and 24 Hours (AUC[0-8], AUC[0-12], AUC[0-24]) of Vemurafenib | 0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19 | Area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to 8, 12, and 24 hours (AUC\[0-8\], AUC\[0-12\], AUC\[0-24\], respectively). |
| Cmax of Probe Parent Drugs and Their Metabolites on Day 1 | Day 1: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours | Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite. |
| Cmax of Probe Parent Drugs and Their Metabolites on Day 20 | Day 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours | Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite. |
| Cmax of Vemurafenib | 0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19 | — |
| Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 | Day 1: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours | Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite. |
| Tmax of Probe Parent Drugs and Their Metabolites on Day 20 | Day 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours | Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite. |
| Tmax of Vemurafenib | 0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | Screening up to approximately 3.5 years (assessed at Screening, Day 1 of Cycle 3 thereafter Day 1 of every other cycle [every 2 months] and at end of study) | Duration of response was defined as the time interval between the date of the earliest qualifying response and the date of disease progression (PD) or death, only for those participants whose best overall response was CR or PR, as assessed by investigator. CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must decrease to normal (short axis \<10 mm). PR was defined as a 30% decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter. PD was defined as at least 20% increase in the sum of diameters of target lesions compared to Nadir (smallest sum of diameters on-study), unequivocal progression of existing non-target lesions, or presence of new lesion. |
| Time to Response | Screening up to approximately 3.5 years (assessed at Screening, Day 1 of cycle 3 thereafter Day 1 of every other cycle [every 2 months] and at end of study) | Time to response was defined as the interval between the date of the first treatment and the date of the first documentation of confirmed CR or PR (as assessed by investigator), whichever occurred first. CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must decrease to normal (short axis \<10 mm). PR was defined as a 30% decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter. |
| Progression-Free Survival (PFS) | Screening up to approximately 3.5 years (assessed at Screening, Day 1 of cycle 3 thereafter Day 1 of every other cycle [every 2 months] and at end of study) | PFS was defined the time interval between the date of the first treatment and the date of progression or death from any cause, whichever occurred first. Deaths that occurred in participants without disease progression were to be considered to be a PFS event on the date of death. Participants who neither progressed nor died were to be censored on the date of the last evaluable tumor assessment prior to the data cutoff date. PD, as assessed by investigator, was defined as at least 20% increase in the sum of diameters of target lesions compared to Nadir (smallest sum of diameters on-study), unequivocal progression of existing non-target lesions, or presence of new lesion. |
| Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) | Screening up to approximately 3.5 years (assessed at Screening, Day 1 of Cycle 3 thereafter Day 1 of every other cycle [every 2 months] and at end of study) | 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, 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) must decrease to normal (short axis less than \[\<\] 10 millimeter \[mm\]). PR was defined as a 30% 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 CR or PR are reported. |
Countries
United States
Participant flow
Pre-assignment details
The five probe parent drugs used in the study were caffeine (metabolite: paraxanthine), S-warfarin (no metabolite), omeprazole (metabolite: hydroxy \[OH\]-omeprazole), dextromethorphan (metabolite: dextrorphan), and midazolam (metabolite: OH-midazolam).
Participants by arm
| Arm | Count |
|---|---|
| Vemurafenib Single oral doses of 5 probe drugs (caffeine 200 mg tablet, warfarin 10 mg tablet \[with Vitamin K 10 mg {2\*5 mg tablets}\], omeprazole 40 mg capsule, dextromethorphan 30 mg syrup, and midazolam 0.075 mg/kg syrup) on Day 1, followed by 5-day washout. Vemurafenib 960 mg (4\*240 mg film-coated tablets) orally twice daily on Day 6 to Day 19. Single oral doses of 5 probe drugs co-administered with vemurafenib 960 mg on Day 20, followed by vemurafenib 960 mg orally twice daily up to Day 28 and then vemurafenib 960 mg orally twice daily continuously in 28-day cycles until disease progression, toxicity, withdrawal of consent, loss to follow-up, or death (whichever occurred first). | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse event or Intercurrent Illness | 1 |
| Overall Study | Began Taking Commercially Available Drug | 2 |
| Overall Study | Death | 1 |
| Overall Study | Insufficient Therapeutic Response | 20 |
| Overall Study | Withdrew Consent | 1 |
Baseline characteristics
| Characteristic | Vemurafenib |
|---|---|
| Age, Continuous | 52.0 years STANDARD_DEVIATION 13.73 |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 25 / 25 |
| serious Total, serious adverse events | 12 / 25 |
Outcome results
Primary
Apparent Elimination Half-Life in Plasma (t1/2) of Probe Parent Drugs and Their Metabolites on Day 1
Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite.
Time frame: Day 1: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours
Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vemurafenib | Apparent Elimination Half-Life in Plasma (t1/2) of Probe Parent Drugs and Their Metabolites on Day 1 | Caffeine - t1/2 | 6.7 hours | Standard Deviation 3.42 |
| Vemurafenib | Apparent Elimination Half-Life in Plasma (t1/2) of Probe Parent Drugs and Their Metabolites on Day 1 | Paraxanthine - t1/2 | 18.5 hours | Standard Deviation 24.84 |
| Vemurafenib | Apparent Elimination Half-Life in Plasma (t1/2) of Probe Parent Drugs and Their Metabolites on Day 1 | S-Warfarin - t1/2 | 42.3 hours | Standard Deviation 18.16 |
| Vemurafenib | Apparent Elimination Half-Life in Plasma (t1/2) of Probe Parent Drugs and Their Metabolites on Day 1 | Omeprazole - t1/2 | 2.0 hours | Standard Deviation 1.65 |
| Vemurafenib | Apparent Elimination Half-Life in Plasma (t1/2) of Probe Parent Drugs and Their Metabolites on Day 1 | OH-Omeprazole - t1/2 | 2.6 hours | Standard Deviation 1.9 |
| Vemurafenib | Apparent Elimination Half-Life in Plasma (t1/2) of Probe Parent Drugs and Their Metabolites on Day 1 | Dextromethorphan - t1/2 | 9.08 hours | Standard Deviation 2.211 |
| Vemurafenib | Apparent Elimination Half-Life in Plasma (t1/2) of Probe Parent Drugs and Their Metabolites on Day 1 | Dextrorphan - t1/2 | 4.08 hours | Standard Deviation 1.612 |
| Vemurafenib | Apparent Elimination Half-Life in Plasma (t1/2) of Probe Parent Drugs and Their Metabolites on Day 1 | Midazolam - t1/2 | 5.06 hours | Standard Deviation 1.787 |
| Vemurafenib | Apparent Elimination Half-Life in Plasma (t1/2) of Probe Parent Drugs and Their Metabolites on Day 1 | OH-Midazolam - t1/2 | 5.46 hours | Standard Deviation 2.749 |
Primary
Apparent Plasma Clearance (CL/F) of Probe Parent Drugs on Day 1
Drug clearance was a quantitative measure of the rate at which a drug substance was removed from the body. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed.
Time frame: Day 1: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours
Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vemurafenib | Apparent Plasma Clearance (CL/F) of Probe Parent Drugs on Day 1 | Caffeine - CL/F (n = 19) | 4.2 milliliters per hour (mL/h) | Standard Deviation 2.03 |
| Vemurafenib | Apparent Plasma Clearance (CL/F) of Probe Parent Drugs on Day 1 | S-Warfarin - CL/F (n = 20) | 622.4 milliliters per hour (mL/h) | Standard Deviation 184.13 |
| Vemurafenib | Apparent Plasma Clearance (CL/F) of Probe Parent Drugs on Day 1 | Omeprazole - CL/F (n = 20) | 0.035 milliliters per hour (mL/h) | Standard Deviation 0.035 |
| Vemurafenib | Apparent Plasma Clearance (CL/F) of Probe Parent Drugs on Day 1 | Dextromethorphan - CL/F (n = 20) | 4108.04 milliliters per hour (mL/h) | Standard Deviation 4117.517 |
| Vemurafenib | Apparent Plasma Clearance (CL/F) of Probe Parent Drugs on Day 1 | Midazolam - CL/F (n = 20) | 72199.55 milliliters per hour (mL/h) | Standard Deviation 35742.23 |
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to 8, 12, and 24 Hours (AUC[0-8], AUC[0-12], AUC[0-24]) of Vemurafenib
Area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to 8, 12, and 24 hours (AUC\[0-8\], AUC\[0-12\], AUC\[0-24\], respectively).
Time frame: 0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19
Population: Primary PK analysis population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vemurafenib | Area Under the Plasma Concentration-Time Curve From Time Zero to 8, 12, and 24 Hours (AUC[0-8], AUC[0-12], AUC[0-24]) of Vemurafenib | AUC(0-8) | 422 micrograms*hour/milliliter (mcg*h/mL) | Standard Deviation 121 |
| Vemurafenib | Area Under the Plasma Concentration-Time Curve From Time Zero to 8, 12, and 24 Hours (AUC[0-8], AUC[0-12], AUC[0-24]) of Vemurafenib | AUC(0-12) | 601 micrograms*hour/milliliter (mcg*h/mL) | Standard Deviation 170 |
| Vemurafenib | Area Under the Plasma Concentration-Time Curve From Time Zero to 8, 12, and 24 Hours (AUC[0-8], AUC[0-12], AUC[0-24]) of Vemurafenib | AUC(0-24) | 1176 micrograms*hour/milliliter (mcg*h/mL) | Standard Deviation 368 |
Primary
AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1
AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. AUC(0-inf) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero extrapolated to infinity. Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin, as S-warfarin does not have a metabolite.
Time frame: Day 1: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours
Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vemurafenib | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | Caffeine - AUC(0-last) (n = 19) | 56350.1 nanograms*hour per milliliter (ng*hr/mL) | Standard Deviation 24744.07 |
| Vemurafenib | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | Caffeine - AUC(0-inf) (n = 19) | 58337.5 nanograms*hour per milliliter (ng*hr/mL) | Standard Deviation 25287.72 |
| Vemurafenib | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | Paraxanthine - AUC(0-last) (n = 19) | 45584.3 nanograms*hour per milliliter (ng*hr/mL) | Standard Deviation 15667.21 |
| Vemurafenib | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | Paraxanthine - AUC(0-inf) (n = 19) | 47589.5 nanograms*hour per milliliter (ng*hr/mL) | Standard Deviation 16667.35 |
| Vemurafenib | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | S-Warfarin - AUC(0-last) (n = 20) | 14964.5 nanograms*hour per milliliter (ng*hr/mL) | Standard Deviation 4566.8 |
| Vemurafenib | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | S-Warfarin - AUC(0-inf) (n = 20) | 17832.5 nanograms*hour per milliliter (ng*hr/mL) | Standard Deviation 6785.62 |
| Vemurafenib | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | Omeprazole - AUC(0-last) (n = 20) | 3110.4 nanograms*hour per milliliter (ng*hr/mL) | Standard Deviation 2956.3 |
| Vemurafenib | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | Omeprazole - AUC(0-inf) (n = 20) | 3181.0 nanograms*hour per milliliter (ng*hr/mL) | Standard Deviation 3107.71 |
| Vemurafenib | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | OH-Omeprazole - AUC(0-last) (n = 20) | 1187.0 nanograms*hour per milliliter (ng*hr/mL) | Standard Deviation 353.49 |
| Vemurafenib | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | OH-Omeprazole - AUC(0-inf) (n = 20) | 1215.3 nanograms*hour per milliliter (ng*hr/mL) | Standard Deviation 398.67 |
| Vemurafenib | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | Dextromethorphan - AUC(0-last) (n = 20) | 28.37 nanograms*hour per milliliter (ng*hr/mL) | Standard Deviation 45.677 |
| Vemurafenib | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | Dextromethorphan - AUC(0-inf) (n = 20) | 29.79 nanograms*hour per milliliter (ng*hr/mL) | Standard Deviation 48.159 |
| Vemurafenib | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | Dextrorphan - AUC(0-last) (n = 20) | 26.76 nanograms*hour per milliliter (ng*hr/mL) | Standard Deviation 19.368 |
| Vemurafenib | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | Dextrorphan - AUC(0-inf) (n = 20) | 29.34 nanograms*hour per milliliter (ng*hr/mL) | Standard Deviation 19.865 |
| Vemurafenib | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | Midazolam - AUC(0-last) (n = 20) | 100.18 nanograms*hour per milliliter (ng*hr/mL) | Standard Deviation 53.949 |
| Vemurafenib | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | Midazolam - AUC(0-inf) (n = 20) | 103.57 nanograms*hour per milliliter (ng*hr/mL) | Standard Deviation 55.767 |
| Vemurafenib | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | OH-Midazolam - AUC(0-last) (n = 20) | 42.96 nanograms*hour per milliliter (ng*hr/mL) | Standard Deviation 22.197 |
| Vemurafenib | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | OH-Midazolam - AUC(0-inf) (n = 20) | 44.70 nanograms*hour per milliliter (ng*hr/mL) | Standard Deviation 22.632 |
Primary
AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20
AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. AUC(0-inf) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero extrapolated to infinity. Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin, as S-warfarin does not have a metabolite.
Time frame: Day 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours
Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vemurafenib | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | Caffeine - AUC(0-last) (n = 19) | 140991.9 ng*hr/mL | Standard Deviation 56983.62 |
| Vemurafenib | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | Caffeine - AUC(0-inf) (n = 19) | 161490.6 ng*hr/mL | Standard Deviation 81139.12 |
| Vemurafenib | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | Paraxanthine - AUC(0-last) (n = 19) | 51344.3 ng*hr/mL | Standard Deviation 14888.54 |
| Vemurafenib | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | Paraxanthine - AUC(0-inf) (n = 19) | 55060.5 ng*hr/mL | Standard Deviation 15481.99 |
| Vemurafenib | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | S-Warfarin - AUC(0-last) (n = 20) | 17804.4 ng*hr/mL | Standard Deviation 5956.35 |
| Vemurafenib | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | S-Warfarin - AUC(0-inf) (n = 20) | 22233.3 ng*hr/mL | Standard Deviation 9485.43 |
| Vemurafenib | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | Omeprazole - AUC(0-last) (n = 20) | 3155.6 ng*hr/mL | Standard Deviation 3090.03 |
| Vemurafenib | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | Omeprazole - AUC(0-inf) (n = 20) | 3224.9 ng*hr/mL | Standard Deviation 3200.67 |
| Vemurafenib | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | OH-Omeprazole - AUC(0-last) (n = 20) | 1370.2 ng*hr/mL | Standard Deviation 370.57 |
| Vemurafenib | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | OH-Omeprazole - AUC(0-inf) (n = 20) | 1409.9 ng*hr/mL | Standard Deviation 398.39 |
| Vemurafenib | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | Dextromethorphan - AUC(0-last) (n = 20) | 39.33 ng*hr/mL | Standard Deviation 56.972 |
| Vemurafenib | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | Dextromethorphan - AUC(0-inf) (n = 20) | 41.56 ng*hr/mL | Standard Deviation 62.027 |
| Vemurafenib | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | Dextrorphan - AUC(0-last) (n = 20) | 37.74 ng*hr/mL | Standard Deviation 23.402 |
| Vemurafenib | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | Dextrorphan - AUC(0-inf) (n = 20) | 40.85 ng*hr/mL | Standard Deviation 24.333 |
| Vemurafenib | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | Midazolam - AUC(0-last) (n = 20) | 67.70 ng*hr/mL | Standard Deviation 50.773 |
| Vemurafenib | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | Midazolam - AUC(0-inf) (n = 20) | 69.82 ng*hr/mL | Standard Deviation 52.705 |
| Vemurafenib | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | OH-Midazolam - AUC(0-last) (n = 20) | 59.78 ng*hr/mL | Standard Deviation 34.419 |
| Vemurafenib | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | OH-Midazolam - AUC(0-inf) (n = 20) | 64.25 ng*hr/mL | Standard Deviation 35.604 |
Primary
CL/F of Probe Parent Drugs on Day 20
Drug clearance was a quantitative measure of the rate at which a drug substance was removed from the body. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed.
Time frame: Day 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours
Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vemurafenib | CL/F of Probe Parent Drugs on Day 20 | Caffeine - CL/F (n = 19) | 1.6 mL/h | Standard Deviation 0.77 |
| Vemurafenib | CL/F of Probe Parent Drugs on Day 20 | S-Warfarin - CL/F (n = 20) | 513.5 mL/h | Standard Deviation 168.97 |
| Vemurafenib | CL/F of Probe Parent Drugs on Day 20 | Omeprazole - CL/F (n = 20) | 0.027 mL/h | Standard Deviation 0.02 |
| Vemurafenib | CL/F of Probe Parent Drugs on Day 20 | Dextromethorphan - CL/F (n = 20) | 2921.59 mL/h | Standard Deviation 3060.46 |
| Vemurafenib | CL/F of Probe Parent Drugs on Day 20 | Midazolam - CL/F (n = 20) | 125436.51 mL/h | Standard Deviation 79335.601 |
Primary
Cmax of Probe Parent Drugs and Their Metabolites on Day 1
Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite.
Time frame: Day 1: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours
Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vemurafenib | Cmax of Probe Parent Drugs and Their Metabolites on Day 1 | Caffeine - Cmax (n = 19) | 4768.9 nanograms per milliliter (ng/mL) | Standard Deviation 1108.43 |
| Vemurafenib | Cmax of Probe Parent Drugs and Their Metabolites on Day 1 | Paraxanthine - Cmax (n = 19) | 1839.1 nanograms per milliliter (ng/mL) | Standard Deviation 477.75 |
| Vemurafenib | Cmax of Probe Parent Drugs and Their Metabolites on Day 1 | S-Warfarin - Cmax (n = 20) | 469.4 nanograms per milliliter (ng/mL) | Standard Deviation 127.22 |
| Vemurafenib | Cmax of Probe Parent Drugs and Their Metabolites on Day 1 | Omeprazole - Cmax (n = 20) | 913.7 nanograms per milliliter (ng/mL) | Standard Deviation 610.63 |
| Vemurafenib | Cmax of Probe Parent Drugs and Their Metabolites on Day 1 | OH-Omeprazole - Cmax (n = 20) | 331.3 nanograms per milliliter (ng/mL) | Standard Deviation 127.6 |
| Vemurafenib | Cmax of Probe Parent Drugs and Their Metabolites on Day 1 | Dextromethorphan - Cmax (n = 20) | 3.38 nanograms per milliliter (ng/mL) | Standard Deviation 4.236 |
| Vemurafenib | Cmax of Probe Parent Drugs and Their Metabolites on Day 1 | Dextrorphan - Cmax (n = 20) | 6.49 nanograms per milliliter (ng/mL) | Standard Deviation 5.041 |
| Vemurafenib | Cmax of Probe Parent Drugs and Their Metabolites on Day 1 | Midazolam - Cmax (n = 20) | 41.88 nanograms per milliliter (ng/mL) | Standard Deviation 29.197 |
| Vemurafenib | Cmax of Probe Parent Drugs and Their Metabolites on Day 1 | OH-Midazolam - Cmax (n = 20) | 18.54 nanograms per milliliter (ng/mL) | Standard Deviation 9.938 |
Primary
Cmax of Probe Parent Drugs and Their Metabolites on Day 20
Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite.
Time frame: Day 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours
Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vemurafenib | Cmax of Probe Parent Drugs and Their Metabolites on Day 20 | Caffeine - Cmax (n = 19) | 4990.5 ng/mL | Standard Deviation 1005.33 |
| Vemurafenib | Cmax of Probe Parent Drugs and Their Metabolites on Day 20 | Paraxanthine - Cmax (n = 19) | 1154.9 ng/mL | Standard Deviation 446.3 |
| Vemurafenib | Cmax of Probe Parent Drugs and Their Metabolites on Day 20 | S-Warfarin - Cmax (n = 20) | 468.3 ng/mL | Standard Deviation 115.63 |
| Vemurafenib | Cmax of Probe Parent Drugs and Their Metabolites on Day 20 | Omeprazole - Cmax (n = 20) | 945.8 ng/mL | Standard Deviation 535.41 |
| Vemurafenib | Cmax of Probe Parent Drugs and Their Metabolites on Day 20 | OH-Omeprazole - Cmax (n = 20) | 348.7 ng/mL | Standard Deviation 168.43 |
| Vemurafenib | Cmax of Probe Parent Drugs and Their Metabolites on Day 20 | Dextromethorphan - Cmax (n = 20) | 4.19 ng/mL | Standard Deviation 5.342 |
| Vemurafenib | Cmax of Probe Parent Drugs and Their Metabolites on Day 20 | Dextrorphan - Cmax (n = 20) | 7.10 ng/mL | Standard Deviation 4.332 |
| Vemurafenib | Cmax of Probe Parent Drugs and Their Metabolites on Day 20 | Midazolam - Cmax (n = 20) | 26.18 ng/mL | Standard Deviation 13.811 |
| Vemurafenib | Cmax of Probe Parent Drugs and Their Metabolites on Day 20 | OH-Midazolam - Cmax (n = 20) | 22.06 ng/mL | Standard Deviation 10.969 |
Primary
Cmax of Vemurafenib
Time frame: 0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19
Population: Primary PK analysis population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vemurafenib | Cmax of Vemurafenib | 61.7 micrograms per milliliter (mcg/mL) | Standard Deviation 17.2 |
Primary
Geometric Mean Ratio of Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Observed Sampling Time (AUC[0-last]) of Probe Parent Drugs
AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. To assess the potential for drug-drug interactions, the geometric mean ratios and corresponding 90 percent (%) confidence interval (CI) of AUC(0-last) of parent probe drug before (Day 1) and after treatment with vemurafenib (Day 20) was calculated. Ratio and corresponding 90% CI of AUC(0-last) (Day 20/Day 1) for each of the 5 probe drugs is reported.
Time frame: Day 1, 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours
Population: Primary pharmacokinetic (PK) population: all participants who received all planned doses of vemurafenib without dose modification/interruption up to Day 25 and all doses of 5 cocktail probes, without major protocol violation. Number of Participants Analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Vemurafenib | Geometric Mean Ratio of Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Observed Sampling Time (AUC[0-last]) of Probe Parent Drugs | Dextromethorphan (n = 20) | 1.47 ratio |
| Vemurafenib | Geometric Mean Ratio of Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Observed Sampling Time (AUC[0-last]) of Probe Parent Drugs | Caffeine (n = 19) | 2.56 ratio |
| Vemurafenib | Geometric Mean Ratio of Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Observed Sampling Time (AUC[0-last]) of Probe Parent Drugs | Midazolam (n = 20) | 0.61 ratio |
| Vemurafenib | Geometric Mean Ratio of Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Observed Sampling Time (AUC[0-last]) of Probe Parent Drugs | Omeprazole (n = 20) | 1.13 ratio |
| Vemurafenib | Geometric Mean Ratio of Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Observed Sampling Time (AUC[0-last]) of Probe Parent Drugs | S-warfarin (n = 20) | 1.18 ratio |
Primary
Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs
AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. To assess the potential for drug-drug interactions, the geometric mean ratios and corresponding 90% CI of AUC(0-last) and Cmax of metabolites of parent probe drug before (Day 1) and after treatment with vemurafenib (Day 20) was calculated. Ratio and corresponding 90% CI of AUC(0-last) and Cmax (Day 20/Day 1) for each of the 4 probe drug metabolites is reported (paraxanthine \[caffeine metabolite\], dextrorphan \[dextromethorphan metabolite\], OH-midazolam \[midazolam metabolite\], OH-omeprazole (omeprazole metabolite); S-warfarin does not have a metabolite).
Time frame: Day 1, 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for paraxanthine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120, dextrorphan 0.5, 1.5, 2, 12, 18, 48, OH-midazolam 0.08, 0.25, 0.5, 0.75, 2, 10, OH-omeprazole 0.5, 1.5, 2, 2.5, 12, 18 hours
Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Vemurafenib | Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs | Paraxanthine - AUC(0-last) (n = 19) | 1.15 ratio |
| Vemurafenib | Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs | Paraxanthine - Cmax (n = 19) | 0.60 ratio |
| Vemurafenib | Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs | Dextrorphan - AUC(0-last) (n = 20) | 1.46 ratio |
| Vemurafenib | Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs | Dextrorphan - Cmax (n = 20) | 1.21 ratio |
| Vemurafenib | Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs | OH-Midazolam - AUC(0-last) (n = 20) | 1.34 ratio |
| Vemurafenib | Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs | OH-Midazolam - Cmax (n = 20) | 1.23 ratio |
| Vemurafenib | Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs | OH-Omeprazole - AUC(0-last) (n = 20) | 1.16 ratio |
| Vemurafenib | Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs | OH-Omeprazole - Cmax (n = 20) | 1.01 ratio |
Primary
Geometric Mean Ratio of Maximum Plasma Concentration (Cmax) of Probe Parent Drugs
To assess the potential for drug-drug interactions, the geometric mean ratios and corresponding 90% CI of Cmax of parent probe drug before (Day 1) and after treatment with vemurafenib (Day 20) was calculated. Ratio and corresponding 90% CI of Cmax (Day 20/Day 1) for each of the 5 probe drugs is reported.
Time frame: Day 1, 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours
Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Vemurafenib | Geometric Mean Ratio of Maximum Plasma Concentration (Cmax) of Probe Parent Drugs | Caffeine (n = 19) | 1.05 ratio |
| Vemurafenib | Geometric Mean Ratio of Maximum Plasma Concentration (Cmax) of Probe Parent Drugs | Dextromethorphan (n = 20) | 1.36 ratio |
| Vemurafenib | Geometric Mean Ratio of Maximum Plasma Concentration (Cmax) of Probe Parent Drugs | Midazolam (n = 20) | 0.65 ratio |
| Vemurafenib | Geometric Mean Ratio of Maximum Plasma Concentration (Cmax) of Probe Parent Drugs | Omeprazole (n = 20) | 1.17 ratio |
| Vemurafenib | Geometric Mean Ratio of Maximum Plasma Concentration (Cmax) of Probe Parent Drugs | S-warfarin (n = 20) | 1.00 ratio |
Primary
t1/2 of Probe Parent Drugs and Their Metabolites on Day 20
Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite.
Time frame: Day 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours
Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vemurafenib | t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 | Caffeine - t1/2 | 20.6 hours | Standard Deviation 11.94 |
| Vemurafenib | t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 | Paraxanthine - t1/2 | 35.3 hours | Standard Deviation 16.57 |
| Vemurafenib | t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 | S-Warfarin - t1/2 | 47.4 hours | Standard Deviation 21.3 |
| Vemurafenib | t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 | Omeprazole - t1/2 | 2.6 hours | Standard Deviation 2.27 |
| Vemurafenib | t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 | OH-Omeprazole - t1/2 | 3.2 hours | Standard Deviation 2.09 |
| Vemurafenib | t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 | Dextromethorphan - t1/2 | 8.24 hours | Standard Deviation 2.884 |
| Vemurafenib | t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 | Dextrorphan - t1/2 | 4.42 hours | Standard Deviation 1.625 |
| Vemurafenib | t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 | Midazolam - t1/2 | 4.00 hours | Standard Deviation 1.648 |
| Vemurafenib | t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 | OH-Midazolam - t1/2 | 7.94 hours | Standard Deviation 4.581 |
Primary
Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1
Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite.
Time frame: Day 1: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours
Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Vemurafenib | Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 | Caffeine - Tmax (n = 19) | 1.00 hours |
| Vemurafenib | Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 | Paraxanthine - Tmax (n = 19) | 8.00 hours |
| Vemurafenib | Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 | S-Warfarin - Tmax (n = 20) | 3.00 hours |
| Vemurafenib | Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 | Omeprazole - Tmax (n = 20) | 3.00 hours |
| Vemurafenib | Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 | OH-Omeprazole - Tmax (n = 20) | 3.00 hours |
| Vemurafenib | Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 | Dextromethorphan - Tmax (n = 20) | 1.50 hours |
| Vemurafenib | Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 | Dextrorphan - Tmax (n = 20) | 1.50 hours |
| Vemurafenib | Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 | Midazolam - Tmax (n = 20) | 0.50 hours |
| Vemurafenib | Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 | OH-Midazolam - Tmax (n = 20) | 0.50 hours |
Primary
Tmax of Probe Parent Drugs and Their Metabolites on Day 20
Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite.
Time frame: Day 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours
Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Vemurafenib | Tmax of Probe Parent Drugs and Their Metabolites on Day 20 | Caffeine - Tmax (n = 19) | 2.00 hours |
| Vemurafenib | Tmax of Probe Parent Drugs and Their Metabolites on Day 20 | Paraxanthine - Tmax (n = 19) | 24.00 hours |
| Vemurafenib | Tmax of Probe Parent Drugs and Their Metabolites on Day 20 | S-Warfarin - Tmax (n = 20) | 3.00 hours |
| Vemurafenib | Tmax of Probe Parent Drugs and Their Metabolites on Day 20 | Omeprazole - Tmax (n = 20) | 2.5 hours |
| Vemurafenib | Tmax of Probe Parent Drugs and Their Metabolites on Day 20 | OH-Omeprazole - Tmax (n = 20) | 3.00 hours |
| Vemurafenib | Tmax of Probe Parent Drugs and Their Metabolites on Day 20 | Dextromethorphan - Tmax (n = 20) | 1.50 hours |
| Vemurafenib | Tmax of Probe Parent Drugs and Their Metabolites on Day 20 | Dextrorphan - Tmax (n = 20) | 1.50 hours |
| Vemurafenib | Tmax of Probe Parent Drugs and Their Metabolites on Day 20 | Midazolam - Tmax (n = 20) | 0.50 hours |
| Vemurafenib | Tmax of Probe Parent Drugs and Their Metabolites on Day 20 | OH-Midazolam - Tmax (n = 20) | 0.50 hours |
Primary
Tmax of Vemurafenib
Time frame: 0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19
Population: Primary PK analysis population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vemurafenib | Tmax of Vemurafenib | 3.10 hours |
Primary
Trough Plasma Concentration (Cmin) of Vemurafenib
Time frame: Before morning dose (0 hour) on Day 19
Population: Primary PK analysis population. Here, number of participants analyzed signifies participants with evaluable data for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vemurafenib | Trough Plasma Concentration (Cmin) of Vemurafenib | 54.5 mcg/mL | Standard Deviation 18.55 |
Secondary
Duration of Response
Duration of response was defined as the time interval between the date of the earliest qualifying response and the date of disease progression (PD) or death, only for those participants whose best overall response was CR or PR, as assessed by investigator. CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must decrease to normal (short axis \<10 mm). PR was defined as a 30% decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter. PD was defined as at least 20% increase in the sum of diameters of target lesions compared to Nadir (smallest sum of diameters on-study), unequivocal progression of existing non-target lesions, or presence of new lesion.
Time frame: Screening up to approximately 3.5 years (assessed at Screening, Day 1 of Cycle 3 thereafter Day 1 of every other cycle [every 2 months] and at end of study)
Population: The 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, 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) must decrease to normal (short axis less than \[\<\] 10 millimeter \[mm\]). PR was defined as a 30% 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 CR or PR are reported.
Time frame: Screening up to approximately 3.5 years (assessed at Screening, Day 1 of Cycle 3 thereafter Day 1 of every other cycle [every 2 months] and at end of study)
Population: Efficacy population included all enrolled participants who received any vemurafenib and had at least one post-baseline tumor assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vemurafenib | Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) | 44 percentage of participants |
Secondary
Progression-Free Survival (PFS)
PFS was defined the time interval between the date of the first treatment and the date of progression or death from any cause, whichever occurred first. Deaths that occurred in participants without disease progression were to be considered to be a PFS event on the date of death. Participants who neither progressed nor died were to be censored on the date of the last evaluable tumor assessment prior to the data cutoff date. PD, as assessed by investigator, was defined as at least 20% increase in the sum of diameters of target lesions compared to Nadir (smallest sum of diameters on-study), unequivocal progression of existing non-target lesions, or presence of new lesion.
Time frame: Screening up to approximately 3.5 years (assessed at Screening, Day 1 of cycle 3 thereafter Day 1 of every other cycle [every 2 months] and at end of study)
Population: The data for this outcome measure was not collected as the outcome was removed as per changes in planned analysis (protocol amendment).
Secondary
Time to Response
Time to response was defined as the interval between the date of the first treatment and the date of the first documentation of confirmed CR or PR (as assessed by investigator), whichever occurred first. CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must decrease to normal (short axis \<10 mm). PR was defined as a 30% decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter.
Time frame: Screening up to approximately 3.5 years (assessed at Screening, Day 1 of cycle 3 thereafter Day 1 of every other cycle [every 2 months] and at end of study)
Population: The data for this outcome measure was not collected as the outcome was removed as per changes in planned analysis (protocol amendment).