Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01001299
Recruitment Status : Completed
First Posted : October 26, 2009
Results First Posted : October 5, 2015
Last Update Posted : August 15, 2017
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Malignant Melanoma
Interventions Drug: Drug cocktail
Drug: RO5185426
Enrollment 25
Recruitment Details  
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).
Arm/Group Title Vemurafenib
Hide Arm/Group Description 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).
Period Title: Overall Study
Started 25
Completed 0
Not Completed 25
Reason Not Completed
Insufficient Therapeutic Response             20
Adverse event or Intercurrent Illness             1
Death             1
Began Taking Commercially Available Drug             2
Withdrew Consent             1
Arm/Group Title Vemurafenib
Hide Arm/Group Description 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).
Overall Number of Baseline Participants 25
Hide Baseline Analysis Population Description
Baseline analysis population included all enrolled participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 25 participants
52.0  (13.73)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants
Female
11
  44.0%
Male
14
  56.0%
1.Primary Outcome
Title 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
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 20
Geometric Mean (90% Confidence Interval)
Unit of Measure: ratio
Caffeine (n = 19)
2.56
(2.24 to 2.93)
Dextromethorphan (n = 20)
1.47
(1.21 to 1.78)
Midazolam (n = 20)
0.61
(0.50 to 0.74)
Omeprazole (n = 20)
1.13
(0.92 to 1.37)
S-warfarin (n = 20)
1.18
(1.12 to 1.24)
2.Primary Outcome
Title Geometric Mean Ratio of Maximum Plasma Concentration (Cmax) of Probe Parent Drugs
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 20
Geometric Mean (90% Confidence Interval)
Unit of Measure: ratio
Caffeine (n = 19)
1.05
(0.98 to 1.13)
Dextromethorphan (n = 20)
1.36
(1.07 to 1.72)
Midazolam (n = 20)
0.65
(0.54 to 0.78)
Omeprazole (n = 20)
1.17
(0.92 to 1.49)
S-warfarin (n = 20)
1.00
(0.93 to 1.08)
3.Primary Outcome
Title Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 20
Geometric Mean (90% Confidence Interval)
Unit of Measure: ratio
Paraxanthine – AUC(0-last) (n = 19)
1.15
(0.98 to 1.36)
Paraxanthine – Cmax (n = 19)
0.60
(0.53 to 0.68)
Dextrorphan - AUC(0-last) (n = 20)
1.46
(1.22 to 1.75)
Dextrorphan – Cmax (n = 20)
1.21
(0.97 to 1.51)
OH-Midazolam - AUC(0-last) (n = 20)
1.34
(1.17 to 1.54)
OH-Midazolam – Cmax (n = 20)
1.23
(1.04 to 1.44)
OH-Omeprazole - AUC(0-last) (n = 20)
1.16
(1.06 to 1.28)
OH-Omeprazole – Cmax (n = 20)
1.01
(0.87 to 1.18)
4.Primary Outcome
Title 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
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: nanograms*hour per milliliter (ng*hr/mL)
Caffeine - AUC(0-last) (n = 19) 56350.1  (24744.07)
Caffeine - AUC(0-inf) (n = 19) 58337.5  (25287.72)
Paraxanthine - AUC(0-last) (n = 19) 45584.3  (15667.21)
Paraxanthine - AUC(0-inf) (n = 19) 47589.5  (16667.35)
S-Warfarin - AUC(0-last) (n = 20) 14964.5  (4566.80)
S-Warfarin - AUC(0-inf) (n = 20) 17832.5  (6785.62)
Omeprazole - AUC(0-last) (n = 20) 3110.4  (2956.30)
Omeprazole - AUC(0-inf) (n = 20) 3181.0  (3107.71)
OH-Omeprazole - AUC(0-last) (n = 20) 1187.0  (353.49)
OH-Omeprazole - AUC(0-inf) (n = 20) 1215.3  (398.67)
Dextromethorphan - AUC(0-last) (n = 20) 28.37  (45.677)
Dextromethorphan - AUC(0-inf) (n = 20) 29.79  (48.159)
Dextrorphan - AUC(0-last) (n = 20) 26.76  (19.368)
Dextrorphan - AUC(0-inf) (n = 20) 29.34  (19.865)
Midazolam - AUC(0-last) (n = 20) 100.18  (53.949)
Midazolam - AUC(0-inf) (n = 20) 103.57  (55.767)
OH-Midazolam - AUC(0-last) (n = 20) 42.96  (22.197)
OH-Midazolam - AUC(0-inf) (n = 20) 44.70  (22.632)
5.Primary Outcome
Title AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: ng*hr/mL
Caffeine - AUC(0-last) (n = 19) 140991.9  (56983.62)
Caffeine - AUC(0-inf) (n = 19) 161490.6  (81139.12)
Paraxanthine - AUC(0-last) (n = 19) 51344.3  (14888.54)
Paraxanthine - AUC(0-inf) (n = 19) 55060.5  (15481.99)
S-Warfarin - AUC(0-last) (n = 20) 17804.4  (5956.35)
S-Warfarin - AUC(0-inf) (n = 20) 22233.3  (9485.43)
Omeprazole - AUC(0-last) (n = 20) 3155.6  (3090.03)
Omeprazole - AUC(0-inf) (n = 20) 3224.9  (3200.67)
OH-Omeprazole - AUC(0-last) (n = 20) 1370.2  (370.57)
OH-Omeprazole - AUC(0-inf) (n = 20) 1409.9  (398.39)
Dextromethorphan - AUC(0-last) (n = 20) 39.33  (56.972)
Dextromethorphan - AUC(0-inf) (n = 20) 41.56  (62.027)
Dextrorphan - AUC(0-last) (n = 20) 37.74  (23.402)
Dextrorphan - AUC(0-inf) (n = 20) 40.85  (24.333)
Midazolam - AUC(0-last) (n = 20) 67.70  (50.773)
Midazolam - AUC(0-inf) (n = 20) 69.82  (52.705)
OH-Midazolam - AUC(0-last) (n = 20) 59.78  (34.419)
OH-Midazolam - AUC(0-inf) (n = 20) 64.25  (35.604)
6.Primary Outcome
Title 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
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Primary PK analysis population.
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 21
Mean (Standard Deviation)
Unit of Measure: micrograms*hour/milliliter (mcg*h/mL)
AUC(0-8) 422  (121)
AUC(0-12) 601  (170)
AUC(0-24) 1176  (368)
7.Primary Outcome
Title Cmax of Probe Parent Drugs and Their Metabolites on Day 1
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: nanograms per milliliter (ng/mL)
Caffeine - Cmax (n = 19) 4768.9  (1108.43)
Paraxanthine - Cmax (n = 19) 1839.1  (477.75)
S-Warfarin - Cmax (n = 20) 469.4  (127.22)
Omeprazole - Cmax (n = 20) 913.7  (610.63)
OH-Omeprazole - Cmax (n = 20) 331.3  (127.60)
Dextromethorphan - Cmax (n = 20) 3.38  (4.236)
Dextrorphan - Cmax (n = 20) 6.49  (5.041)
Midazolam - Cmax (n = 20) 41.88  (29.197)
OH-Midazolam - Cmax (n = 20) 18.54  (9.938)
8.Primary Outcome
Title Cmax of Probe Parent Drugs and Their Metabolites on Day 20
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: ng/mL
Caffeine - Cmax (n = 19) 4990.5  (1005.33)
Paraxanthine - Cmax (n = 19) 1154.9  (446.30)
S-Warfarin - Cmax (n = 20) 468.3  (115.63)
Omeprazole - Cmax (n = 20) 945.8  (535.41)
OH-Omeprazole - Cmax (n = 20) 348.7  (168.43)
Dextromethorphan - Cmax (n = 20) 4.19  (5.342)
Dextrorphan - Cmax (n = 20) 7.10  (4.332)
Midazolam - Cmax (n = 20) 26.18  (13.811)
OH-Midazolam - Cmax (n = 20) 22.06  (10.969)
9.Primary Outcome
Title Cmax of Vemurafenib
Hide Description [Not Specified]
Time Frame 0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19
Hide Outcome Measure Data
Hide Analysis Population Description
Primary PK analysis population.
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 21
Mean (Standard Deviation)
Unit of Measure: micrograms per milliliter (mcg/mL)
61.7  (17.2)
10.Primary Outcome
Title Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 20
Median (Full Range)
Unit of Measure: hours
Caffeine - Tmax (n = 19)
1.00
(1.00 to 3.00)
Paraxanthine - Tmax (n = 19)
8.00
(4.00 to 24.00)
S-Warfarin - Tmax (n = 20)
3.00
(1.00 to 6.00)
Omeprazole - Tmax (n = 20)
3.00
(1.00 to 8.00)
OH-Omeprazole - Tmax (n = 20)
3.00
(1.00 to 8.00)
Dextromethorphan - Tmax (n = 20)
1.50
(0.50 to 3.00)
Dextrorphan - Tmax (n = 20)
1.50
(0.50 to 4.00)
Midazolam - Tmax (n = 20)
0.50
(0.25 to 2.00)
OH-Midazolam - Tmax (n = 20)
0.50
(0.25 to 2.00)
11.Primary Outcome
Title Tmax of Probe Parent Drugs and Their Metabolites on Day 20
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 20
Median (Full Range)
Unit of Measure: hours
Caffeine - Tmax (n = 19)
2.00
(1.00 to 122.00)
Paraxanthine - Tmax (n = 19)
24.00
(8.00 to 122.00)
S-Warfarin - Tmax (n = 20)
3.00
(1.00 to 8.00)
Omeprazole - Tmax (n = 20)
2.5
(1.0 to 8.0)
OH-Omeprazole - Tmax (n = 20)
3.00
(1.00 to 8.00)
Dextromethorphan - Tmax (n = 20)
1.50
(0.50 to 3.00)
Dextrorphan - Tmax (n = 20)
1.50
(1.00 to 3.00)
Midazolam - Tmax (n = 20)
0.50
(0.25 to 1.05)
OH-Midazolam - Tmax (n = 20)
0.50
(0.25 to 2.25)
12.Primary Outcome
Title Tmax of Vemurafenib
Hide Description [Not Specified]
Time Frame 0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19
Hide Outcome Measure Data
Hide Analysis Population Description
Primary PK analysis population.
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 21
Median (Full Range)
Unit of Measure: hours
3.10
(0.00 to 26.1)
13.Primary Outcome
Title Trough Plasma Concentration (Cmin) of Vemurafenib
Hide Description [Not Specified]
Time Frame Before morning dose (0 hour) on Day 19
Hide Outcome Measure Data
Hide Analysis Population Description
Primary PK analysis population. Here, number of participants analyzed signifies participants with evaluable data for this outcome.
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: mcg/mL
54.5  (18.55)
14.Primary Outcome
Title Apparent Elimination Half-Life in Plasma (t1/2) of Probe Parent Drugs and Their Metabolites on Day 1
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome.
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: hours
Caffeine - t1/2 6.7  (3.42)
Paraxanthine - t1/2 18.5  (24.84)
S-Warfarin - t1/2 42.3  (18.16)
Omeprazole - t1/2 2.0  (1.65)
OH-Omeprazole - t1/2 2.6  (1.90)
Dextromethorphan - t1/2 9.08  (2.211)
Dextrorphan - t1/2 4.08  (1.612)
Midazolam - t1/2 5.06  (1.787)
OH-Midazolam - t1/2 5.46  (2.749)
15.Primary Outcome
Title t1/2 of Probe Parent Drugs and Their Metabolites on Day 20
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome.
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: hours
Caffeine - t1/2 20.6  (11.94)
Paraxanthine - t1/2 35.3  (16.57)
S-Warfarin - t1/2 47.4  (21.30)
Omeprazole - t1/2 2.6  (2.27)
OH-Omeprazole - t1/2 3.2  (2.09)
Dextromethorphan - t1/2 8.24  (2.884)
Dextrorphan - t1/2 4.42  (1.625)
Midazolam - t1/2 4.00  (1.648)
OH-Midazolam - t1/2 7.94  (4.581)
16.Primary Outcome
Title Apparent Plasma Clearance (CL/F) of Probe Parent Drugs on Day 1
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: milliliters per hour (mL/h)
Caffeine - CL/F (n = 19) 4.2  (2.03)
S-Warfarin - CL/F (n = 20) 622.4  (184.13)
Omeprazole - CL/F (n = 20) 0.035  (0.035)
Dextromethorphan - CL/F (n = 20) 4108.04  (4117.517)
Midazolam - CL/F (n = 20) 72199.55  (35742.230)
17.Primary Outcome
Title CL/F of Probe Parent Drugs on Day 20
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category.
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: mL/h
Caffeine - CL/F (n = 19) 1.6  (0.77)
S-Warfarin - CL/F (n = 20) 513.5  (168.97)
Omeprazole - CL/F (n = 20) 0.027  (0.020)
Dextromethorphan - CL/F (n = 20) 2921.59  (3060.460)
Midazolam - CL/F (n = 20) 125436.51  (79335.601)
18.Secondary Outcome
Title Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR)
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy population included all enrolled participants who received any vemurafenib and had at least one post-baseline tumor assessment.
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 25
Measure Type: Number
Unit of Measure: percentage of participants
44
19.Secondary Outcome
Title Duration of Response
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
The data for this outcome measure was not collected as the outcome was removed as per changes in planned analysis (protocol amendment).
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
20.Secondary Outcome
Title Time to Response
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
The data for this outcome measure was not collected as the outcome was removed as per changes in planned analysis (protocol amendment).
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
21.Secondary Outcome
Title Progression-Free Survival (PFS)
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
The data for this outcome measure was not collected as the outcome was removed as per changes in planned analysis (protocol amendment).
Arm/Group Title Vemurafenib
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
Time Frame Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Vemurafenib
Hide Arm/Group Description 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).
All-Cause Mortality
Vemurafenib
Affected / at Risk (%)
Total   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Vemurafenib
Affected / at Risk (%)
Total   12/25 (48.00%) 
Blood and lymphatic system disorders   
Febrile neutropenia * 1  1/25 (4.00%) 
Eye disorders   
Uveitis * 1  1/25 (4.00%) 
Gastrointestinal disorders   
Gastrointestinal haemorrhage * 1  1/25 (4.00%) 
General disorders   
Pyrexia * 1  1/25 (4.00%) 
Investigations   
Blood alkaline phosphatase increased * 1  1/25 (4.00%) 
Metabolism and nutrition disorders   
Dehydration * 1  1/25 (4.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Squamous cell carcinoma of skin * 1  8/25 (32.00%) 
Basal cell carcinoma * 1  3/25 (12.00%) 
Keratoacanthoma * 1  1/25 (4.00%) 
Nervous system disorders   
Cerebrovasular accident * 1  1/25 (4.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 16.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Vemurafenib
Affected / at Risk (%)
Total   25/25 (100.00%) 
Blood and lymphatic system disorders   
Anaemia * 1  7/25 (28.00%) 
Ear and labyrinth disorders   
Ear pain * 1  2/25 (8.00%) 
Eye disorders   
Conjunctivitis * 1  2/25 (8.00%) 
Dry eye * 1  5/25 (20.00%) 
Lacrimation increased * 1  2/25 (8.00%) 
Photophobia * 1  2/25 (8.00%) 
Gastrointestinal disorders   
Abdominal pain * 1  2/25 (8.00%) 
Constipation * 1  2/25 (8.00%) 
Diarrhoea * 1  8/25 (32.00%) 
Nausea * 1  11/25 (44.00%) 
Vomiting * 1  5/25 (20.00%) 
General disorders   
Chills * 1  4/25 (16.00%) 
Fatigue * 1  19/25 (76.00%) 
Influenza like illness * 1  2/25 (8.00%) 
Nodule * 1  2/25 (8.00%) 
Oedema peripheral * 1  7/25 (28.00%) 
Pyrexia * 1  7/25 (28.00%) 
Hepatobiliary disorders   
Hyperbilirubinaemia * 1  2/25 (8.00%) 
Infections and infestations   
Folliculitis * 1  2/25 (8.00%) 
Nasopharyngitis * 1  2/25 (8.00%) 
Oral candidiasis * 1  2/25 (8.00%) 
Upper respiratory tract infection * 1  3/25 (12.00%) 
Urinary tract infection * 1  2/25 (8.00%) 
Injury, poisoning and procedural complications   
Sunburn * 1  4/25 (16.00%) 
Investigations   
Blood alkaline phosphatase increased * 1  3/25 (12.00%) 
Blood bilirubin increased * 1  2/25 (8.00%) 
Blood cholesterol increased * 1  2/25 (8.00%) 
Blood creatinine increased * 1  3/25 (12.00%) 
Gamma-glutamyltransferase increased * 1  4/25 (16.00%) 
Liver function test abnormal * 1  2/25 (8.00%) 
Lymphocyte count decreased * 1  2/25 (8.00%) 
Weight decreased * 1  3/25 (12.00%) 
White blood cell count decreased * 1  3/25 (12.00%) 
Metabolism and nutrition disorders   
Decreased appetite * 1  4/25 (16.00%) 
Dehydration * 1  2/25 (8.00%) 
Hypercholesterolaemia * 1  2/25 (8.00%) 
Hyperglycaemia * 1  2/25 (8.00%) 
Hyperuricaemia * 1  2/25 (8.00%) 
Hypokalaemia * 1  4/25 (16.00%) 
Hyponatraemia * 1  4/25 (16.00%) 
Hypophosphataemia * 1  2/25 (8.00%) 
Hypovolaemia * 1  2/25 (8.00%) 
Musculoskeletal and connective tissue disorders   
Arthralgia * 1  18/25 (72.00%) 
Back pain * 1  2/25 (8.00%) 
Bursitis * 1  2/25 (8.00%) 
Joint stiffness * 1  3/25 (12.00%) 
Muscle spasms * 1  3/25 (12.00%) 
Musculoskeletal pain * 1  3/25 (12.00%) 
Pain in extremity * 1  8/25 (32.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Acrochordon * 1  2/25 (8.00%) 
Skin papilloma * 1  9/25 (36.00%) 
Nervous system disorders   
Dysgeusia * 1  4/25 (16.00%) 
Headache * 1  10/25 (40.00%) 
Hyperaesthesia * 1  2/25 (8.00%) 
Neuropathy peripheral * 1  2/25 (8.00%) 
Psychiatric disorders   
Anxiety * 1  3/25 (12.00%) 
Insomnia * 1  3/25 (12.00%) 
Renal and urinary disorders   
Dysuria * 1  2/25 (8.00%) 
Renal failure acute * 1  2/25 (8.00%) 
Reproductive system and breast disorders   
Gynaecomastia * 1  3/25 (12.00%) 
Nipple swelling * 1  7/25 (28.00%) 
Respiratory, thoracic and mediastinal disorders   
Cough * 1  3/25 (12.00%) 
Upper-airway cough syndrome * 1  2/25 (8.00%) 
Skin and subcutaneous tissue disorders   
Acne * 1  4/25 (16.00%) 
Actinic Keratosis * 1  9/25 (36.00%) 
Blister * 1  2/25 (8.00%) 
Alopecia * 1  12/25 (48.00%) 
Dermal cyst * 1  2/25 (8.00%) 
Dermatitis acneiform * 1  2/25 (8.00%) 
Dry skin * 1  3/25 (12.00%) 
Erythema * 1  2/25 (8.00%) 
Hyperkeratosis * 1  13/25 (52.00%) 
Palmar-plantar erythrodysaesthesia syndrome * 1  4/25 (16.00%) 
Photosensitivity reaction * 1  15/25 (60.00%) 
Pruritus * 1  13/25 (52.00%) 
Rash * 1  7/25 (28.00%) 
Rash maculo-papular * 1  13/25 (52.00%) 
Skin lesion * 1  2/25 (8.00%) 
Vascular disorders   
Hypertension * 1  4/25 (16.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 16.0
The data for ‘Duration of Response’, ‘Time to Response’, and ‘PFS’ was not collected as the outcomes were removed as per changes in planned analysis (protocol amendment).
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Communications
Organization: Hoffmann-La Roche
Phone: 800-821-8590
EMail: genentech@druginfo.com
Layout table for additonal information
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01001299     History of Changes
Other Study ID Numbers: NP22676
First Submitted: October 21, 2009
First Posted: October 26, 2009
Results First Submitted: July 27, 2015
Results First Posted: October 5, 2015
Last Update Posted: August 15, 2017