Trial Outcomes & Findings for A Pharmacokinetic Study of RO5185426 in Combination With a Drug Cocktail in Patients With Metastatic Melanoma (NCT NCT01001299)

Last Updated: 2017-08-15

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

25 participants

Primary outcome timeframe

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

Results posted on

2017-08-15

Participant Flow

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).

Participant milestones

Participant milestones
Measure	Vemurafenib Single oral doses of 5 probe drugs (caffeine 200 milligrams \[mg\] 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 milligrams per kilogram \[mg/kg\] syrup) on Day 1, followed by 5-day washout. Vemurafenib (RO5185426) 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).
Overall Study STARTED	25
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	25

Reasons for withdrawal

Reasons for withdrawal
Measure	Vemurafenib Single oral doses of 5 probe drugs (caffeine 200 milligrams \[mg\] 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 milligrams per kilogram \[mg/kg\] syrup) on Day 1, followed by 5-day washout. Vemurafenib (RO5185426) 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).
Overall Study Insufficient Therapeutic Response	20
Overall Study Adverse event or Intercurrent Illness	1
Overall Study Death	1
Overall Study Began Taking Commercially Available Drug	2
Overall Study Withdrew Consent	1

Baseline Characteristics

A Pharmacokinetic Study of RO5185426 in Combination With a Drug Cocktail in Patients With Metastatic Melanoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Vemurafenib n=25 Participants 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).
Age, Continuous	52.0 years STANDARD_DEVIATION 13.73 • n=5 Participants
Sex: Female, Male Female	11 Participants n=5 Participants
Sex: Female, Male Male	14 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Vemurafenib n=20 Participants 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).
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 Interval 2.24 to 2.93
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 Interval 1.21 to 1.78
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 Interval 0.5 to 0.74
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 Interval 0.92 to 1.37
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 Interval 1.12 to 1.24

PRIMARY outcome

Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.

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.

Outcome measures

Outcome measures
Measure	Vemurafenib n=20 Participants 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).
Geometric Mean Ratio of Maximum Plasma Concentration (Cmax) of Probe Parent Drugs Caffeine (n = 19)	1.05 ratio Interval 0.98 to 1.13
Geometric Mean Ratio of Maximum Plasma Concentration (Cmax) of Probe Parent Drugs Dextromethorphan (n = 20)	1.36 ratio Interval 1.07 to 1.72
Geometric Mean Ratio of Maximum Plasma Concentration (Cmax) of Probe Parent Drugs Midazolam (n = 20)	0.65 ratio Interval 0.54 to 0.78
Geometric Mean Ratio of Maximum Plasma Concentration (Cmax) of Probe Parent Drugs Omeprazole (n = 20)	1.17 ratio Interval 0.92 to 1.49
Geometric Mean Ratio of Maximum Plasma Concentration (Cmax) of Probe Parent Drugs S-warfarin (n = 20)	1.00 ratio Interval 0.93 to 1.08

PRIMARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Vemurafenib n=20 Participants 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).
Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs Paraxanthine - AUC(0-last) (n = 19)	1.15 ratio Interval 0.98 to 1.36
Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs Paraxanthine - Cmax (n = 19)	0.60 ratio Interval 0.53 to 0.68
Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs Dextrorphan - AUC(0-last) (n = 20)	1.46 ratio Interval 1.22 to 1.75
Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs Dextrorphan - Cmax (n = 20)	1.21 ratio Interval 0.97 to 1.51
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 Interval 1.17 to 1.54
Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs OH-Midazolam - Cmax (n = 20)	1.23 ratio Interval 1.04 to 1.44
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 Interval 1.06 to 1.28
Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs OH-Omeprazole - Cmax (n = 20)	1.01 ratio Interval 0.87 to 1.18

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Vemurafenib n=20 Participants 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).
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 nanogramshour per milliliter (nghr/mL) Standard Deviation 24744.07
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 nanogramshour per milliliter (nghr/mL) Standard Deviation 25287.72
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 nanogramshour per milliliter (nghr/mL) Standard Deviation 15667.21
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 nanogramshour per milliliter (nghr/mL) Standard Deviation 16667.35
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 nanogramshour per milliliter (nghr/mL) Standard Deviation 4566.80
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 nanogramshour per milliliter (nghr/mL) Standard Deviation 6785.62
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 nanogramshour per milliliter (nghr/mL) Standard Deviation 2956.30
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 nanogramshour per milliliter (nghr/mL) Standard Deviation 3107.71
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 nanogramshour per milliliter (nghr/mL) Standard Deviation 353.49
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 nanogramshour per milliliter (nghr/mL) Standard Deviation 398.67
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 nanogramshour per milliliter (nghr/mL) Standard Deviation 45.677
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 nanogramshour per milliliter (nghr/mL) Standard Deviation 48.159
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 nanogramshour per milliliter (nghr/mL) Standard Deviation 19.368
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 nanogramshour per milliliter (nghr/mL) Standard Deviation 19.865
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 nanogramshour per milliliter (nghr/mL) Standard Deviation 53.949
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 nanogramshour per milliliter (nghr/mL) Standard Deviation 55.767
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 nanogramshour per milliliter (nghr/mL) Standard Deviation 22.197
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 nanogramshour per milliliter (nghr/mL) Standard Deviation 22.632

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Vemurafenib n=20 Participants 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).
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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 outcome

Timeframe: 0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19

Population: Primary PK analysis population.

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).

Outcome measures

Outcome measures
Measure	Vemurafenib n=21 Participants 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).
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 microgramshour/milliliter (mcgh/mL) Standard Deviation 121
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 microgramshour/milliliter (mcgh/mL) Standard Deviation 170
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 microgramshour/milliliter (mcgh/mL) Standard Deviation 368

PRIMARY outcome

Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.

Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite.

Outcome measures

Outcome measures
Measure	Vemurafenib n=20 Participants 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).
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
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
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
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
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 127.60
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
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
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
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 outcome

Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.

Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite.

Outcome measures

Outcome measures
Measure	Vemurafenib n=20 Participants 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).
Cmax of Probe Parent Drugs and Their Metabolites on Day 20 Caffeine - Cmax (n = 19)	4990.5 ng/mL Standard Deviation 1005.33
Cmax of Probe Parent Drugs and Their Metabolites on Day 20 Paraxanthine - Cmax (n = 19)	1154.9 ng/mL Standard Deviation 446.30
Cmax of Probe Parent Drugs and Their Metabolites on Day 20 S-Warfarin - Cmax (n = 20)	468.3 ng/mL Standard Deviation 115.63
Cmax of Probe Parent Drugs and Their Metabolites on Day 20 Omeprazole - Cmax (n = 20)	945.8 ng/mL Standard Deviation 535.41
Cmax of Probe Parent Drugs and Their Metabolites on Day 20 OH-Omeprazole - Cmax (n = 20)	348.7 ng/mL Standard Deviation 168.43
Cmax of Probe Parent Drugs and Their Metabolites on Day 20 Dextromethorphan - Cmax (n = 20)	4.19 ng/mL Standard Deviation 5.342
Cmax of Probe Parent Drugs and Their Metabolites on Day 20 Dextrorphan - Cmax (n = 20)	7.10 ng/mL Standard Deviation 4.332
Cmax of Probe Parent Drugs and Their Metabolites on Day 20 Midazolam - Cmax (n = 20)	26.18 ng/mL Standard Deviation 13.811
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 outcome

Timeframe: 0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19

Population: Primary PK analysis population.

Outcome measures

Outcome measures
Measure	Vemurafenib n=21 Participants 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).
Cmax of Vemurafenib	61.7 micrograms per milliliter (mcg/mL) Standard Deviation 17.2

PRIMARY outcome

Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.

Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite.

Outcome measures

Outcome measures
Measure	Vemurafenib n=20 Participants 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).
Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 Caffeine - Tmax (n = 19)	1.00 hours Interval 1.0 to 3.0
Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 Paraxanthine - Tmax (n = 19)	8.00 hours Interval 4.0 to 24.0
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 Interval 1.0 to 6.0
Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 Omeprazole - Tmax (n = 20)	3.00 hours Interval 1.0 to 8.0
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 Interval 1.0 to 8.0
Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 Dextromethorphan - Tmax (n = 20)	1.50 hours Interval 0.5 to 3.0
Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 Dextrorphan - Tmax (n = 20)	1.50 hours Interval 0.5 to 4.0
Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 Midazolam - Tmax (n = 20)	0.50 hours Interval 0.25 to 2.0
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 Interval 0.25 to 2.0

PRIMARY outcome

Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.

Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite.

Outcome measures

Outcome measures
Measure	Vemurafenib n=20 Participants 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).
Tmax of Probe Parent Drugs and Their Metabolites on Day 20 Caffeine - Tmax (n = 19)	2.00 hours Interval 1.0 to 122.0
Tmax of Probe Parent Drugs and Their Metabolites on Day 20 Paraxanthine - Tmax (n = 19)	24.00 hours Interval 8.0 to 122.0
Tmax of Probe Parent Drugs and Their Metabolites on Day 20 S-Warfarin - Tmax (n = 20)	3.00 hours Interval 1.0 to 8.0
Tmax of Probe Parent Drugs and Their Metabolites on Day 20 Omeprazole - Tmax (n = 20)	2.5 hours Interval 1.0 to 8.0
Tmax of Probe Parent Drugs and Their Metabolites on Day 20 OH-Omeprazole - Tmax (n = 20)	3.00 hours Interval 1.0 to 8.0
Tmax of Probe Parent Drugs and Their Metabolites on Day 20 Dextromethorphan - Tmax (n = 20)	1.50 hours Interval 0.5 to 3.0
Tmax of Probe Parent Drugs and Their Metabolites on Day 20 Dextrorphan - Tmax (n = 20)	1.50 hours Interval 1.0 to 3.0
Tmax of Probe Parent Drugs and Their Metabolites on Day 20 Midazolam - Tmax (n = 20)	0.50 hours Interval 0.25 to 1.05
Tmax of Probe Parent Drugs and Their Metabolites on Day 20 OH-Midazolam - Tmax (n = 20)	0.50 hours Interval 0.25 to 2.25

PRIMARY outcome

Timeframe: 0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19

Population: Primary PK analysis population.

Outcome measures

Outcome measures
Measure	Vemurafenib n=21 Participants 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).
Tmax of Vemurafenib	3.10 hours Interval 0.0 to 26.1

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Vemurafenib n=20 Participants 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).
Trough Plasma Concentration (Cmin) of Vemurafenib	54.5 mcg/mL Standard Deviation 18.55

PRIMARY outcome

Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome.

Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite.

Outcome measures

Outcome measures
Measure	Vemurafenib n=20 Participants 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).
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
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
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
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
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 1.90
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
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
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
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 outcome

Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome.

Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite.

Outcome measures

Outcome measures
Measure	Vemurafenib n=20 Participants 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).
t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 Caffeine - t1/2	20.6 hours Standard Deviation 11.94
t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 Paraxanthine - t1/2	35.3 hours Standard Deviation 16.57
t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 S-Warfarin - t1/2	47.4 hours Standard Deviation 21.30
t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 Omeprazole - t1/2	2.6 hours Standard Deviation 2.27
t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 OH-Omeprazole - t1/2	3.2 hours Standard Deviation 2.09
t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 Dextromethorphan - t1/2	8.24 hours Standard Deviation 2.884
t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 Dextrorphan - t1/2	4.42 hours Standard Deviation 1.625
t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 Midazolam - t1/2	4.00 hours Standard Deviation 1.648
t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 OH-Midazolam - t1/2	7.94 hours Standard Deviation 4.581

PRIMARY outcome

Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.

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.

Outcome measures

Outcome measures
Measure	Vemurafenib n=20 Participants 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).
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
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
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
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
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 35742.230

PRIMARY outcome

Population: Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.

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.

Outcome measures

Outcome measures
Measure	Vemurafenib n=20 Participants 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).
CL/F of Probe Parent Drugs on Day 20 Caffeine - CL/F (n = 19)	1.6 mL/h Standard Deviation 0.77
CL/F of Probe Parent Drugs on Day 20 S-Warfarin - CL/F (n = 20)	513.5 mL/h Standard Deviation 168.97
CL/F of Probe Parent Drugs on Day 20 Omeprazole - CL/F (n = 20)	0.027 mL/h Standard Deviation 0.020
CL/F of Probe Parent Drugs on Day 20 Dextromethorphan - CL/F (n = 20)	2921.59 mL/h Standard Deviation 3060.460
CL/F of Probe Parent Drugs on Day 20 Midazolam - CL/F (n = 20)	125436.51 mL/h Standard Deviation 79335.601

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Vemurafenib n=25 Participants 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).
Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR)	44 percentage of participants

SECONDARY outcome

Timeframe: 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).

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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).

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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).

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.

Outcome measures

Outcome data not reported

Adverse Events

Vemurafenib

Serious events: 12 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Vemurafenib n=25 participants at risk 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).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	32.0% 8/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	12.0% 3/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Keratoacanthoma	4.0% 1/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Blood and lymphatic system disorders Febrile neutropenia	4.0% 1/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Eye disorders Uveitis	4.0% 1/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Gastrointestinal disorders Gastrointestinal haemorrhage	4.0% 1/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
General disorders Pyrexia	4.0% 1/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Investigations Blood alkaline phosphatase increased	4.0% 1/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Metabolism and nutrition disorders Dehydration	4.0% 1/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Nervous system disorders Cerebrovasular accident	4.0% 1/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)

Other adverse events

Other adverse events
Measure	Vemurafenib n=25 participants at risk 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).
Blood and lymphatic system disorders Anaemia	28.0% 7/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Ear and labyrinth disorders Ear pain	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Eye disorders Conjunctivitis	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Eye disorders Dry eye	20.0% 5/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Eye disorders Lacrimation increased	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Eye disorders Photophobia	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Gastrointestinal disorders Abdominal pain	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Gastrointestinal disorders Constipation	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Gastrointestinal disorders Diarrhoea	32.0% 8/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Gastrointestinal disorders Nausea	44.0% 11/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Gastrointestinal disorders Vomiting	20.0% 5/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
General disorders Chills	16.0% 4/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
General disorders Fatigue	76.0% 19/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
General disorders Influenza like illness	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
General disorders Nodule	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
General disorders Oedema peripheral	28.0% 7/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
General disorders Pyrexia	28.0% 7/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Hepatobiliary disorders Hyperbilirubinaemia	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Infections and infestations Folliculitis	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Infections and infestations Nasopharyngitis	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Infections and infestations Oral candidiasis	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Infections and infestations Upper respiratory tract infection	12.0% 3/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Infections and infestations Urinary tract infection	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Injury, poisoning and procedural complications Sunburn	16.0% 4/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Investigations Blood alkaline phosphatase increased	12.0% 3/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Investigations Blood bilirubin increased	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Investigations Blood cholesterol increased	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Investigations Blood creatinine increased	12.0% 3/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Investigations Gamma-glutamyltransferase increased	16.0% 4/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Investigations Liver function test abnormal	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Investigations Lymphocyte count decreased	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Investigations Weight decreased	12.0% 3/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Investigations White blood cell count decreased	12.0% 3/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Metabolism and nutrition disorders Decreased appetite	16.0% 4/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Metabolism and nutrition disorders Dehydration	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Metabolism and nutrition disorders Hypercholesterolaemia	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Metabolism and nutrition disorders Hyperglycaemia	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Metabolism and nutrition disorders Hyperuricaemia	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Metabolism and nutrition disorders Hypokalaemia	16.0% 4/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Metabolism and nutrition disorders Hyponatraemia	16.0% 4/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Metabolism and nutrition disorders Hypophosphataemia	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Metabolism and nutrition disorders Hypovolaemia	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Musculoskeletal and connective tissue disorders Arthralgia	72.0% 18/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Musculoskeletal and connective tissue disorders Back pain	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Musculoskeletal and connective tissue disorders Bursitis	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Musculoskeletal and connective tissue disorders Joint stiffness	12.0% 3/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Musculoskeletal and connective tissue disorders Muscle spasms	12.0% 3/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Musculoskeletal and connective tissue disorders Musculoskeletal pain	12.0% 3/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Musculoskeletal and connective tissue disorders Pain in extremity	32.0% 8/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Acrochordon	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Skin papilloma	36.0% 9/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Nervous system disorders Dysgeusia	16.0% 4/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Nervous system disorders Headache	40.0% 10/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Nervous system disorders Hyperaesthesia	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Nervous system disorders Neuropathy peripheral	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Psychiatric disorders Anxiety	12.0% 3/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Psychiatric disorders Insomnia	12.0% 3/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Renal and urinary disorders Dysuria	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Renal and urinary disorders Renal failure acute	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Reproductive system and breast disorders Gynaecomastia	12.0% 3/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Reproductive system and breast disorders Nipple swelling	28.0% 7/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Respiratory, thoracic and mediastinal disorders Cough	12.0% 3/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Respiratory, thoracic and mediastinal disorders Upper-airway cough syndrome	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Skin and subcutaneous tissue disorders Acne	16.0% 4/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Skin and subcutaneous tissue disorders Actinic Keratosis	36.0% 9/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Skin and subcutaneous tissue disorders Blister	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Skin and subcutaneous tissue disorders Alopecia	48.0% 12/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Skin and subcutaneous tissue disorders Dermal cyst	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Skin and subcutaneous tissue disorders Dermatitis acneiform	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Skin and subcutaneous tissue disorders Dry skin	12.0% 3/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Skin and subcutaneous tissue disorders Erythema	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Skin and subcutaneous tissue disorders Hyperkeratosis	52.0% 13/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	16.0% 4/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Skin and subcutaneous tissue disorders Photosensitivity reaction	60.0% 15/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Skin and subcutaneous tissue disorders Pruritus	52.0% 13/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Skin and subcutaneous tissue disorders Rash	28.0% 7/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Skin and subcutaneous tissue disorders Rash maculo-papular	52.0% 13/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Skin and subcutaneous tissue disorders Skin lesion	8.0% 2/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Vascular disorders Hypertension	16.0% 4/25 • Up to 28 days after the last dose of study drug (median treatment duration: 144 days)

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER