A Pharmacokinetic Study of RO5185426 in Combination With a Drug Cocktail in Patients With Metastatic Melanoma
Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT01001299
Collaborator
(none)
25
5
1
27
5
0.2
Study Details
Study Description
Brief Summary
This open-label single-arm study will evaluate the effect of RO5185426 [RG7204; PLEXXIKON:
PLX4032] on the pharmacokinetics of five CYP450 substrates (caffeine, warfarin + vitamin K, omeprazole, dextromethorphan, midazolam) administered as a drug cocktail to patients with metastatic melanoma. The study will also evaluate efficacy and safety of RO5185426. On day 1, patients will receive the drug cocktail. On days 6 to 19, patients will receive RO5185426 twice daily. On day 20, patients will receive RO5185426 and the drug cocktail and on days 21 to 25, patients will receive RO5185426. Assessments will be made at regular intervals during the dosing periods and at follow-up. Patients may continue on study treatment (RO5185426) until the development of progressive disease or unacceptable toxicity. Target sample size <50.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
25 participants
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Multi-center, Open-label, Study to Investigate the Pharmacokinetic Interaction of RO5185426 With a "Cocktail" of Five Probe Drugs for CYP450 Dependent Metabolism in Patients With Previously Treated and Untreated Metastatic Melanoma
Actual Study Start Date
:
Nov 30, 2009
Actual Primary Completion Date
:
Feb 29, 2012
Actual Study Completion Date
:
Feb 29, 2012
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Single arm
|
Drug: Drug cocktail
Drug cocktail (caffeine, warfarin + vitamin K, omeprazole, dextromethorphan, midazolam) orally once daily, day 1 and day 20
Drug: RO5185426
960 mg orally twice daily
|
Outcome Measures
Primary Outcome Measures
- Geometric Mean Ratio of Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Observed Sampling Time (AUC[0-last]) of Probe Parent Drugs [Day 1, 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours]
AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. To assess the potential for drug-drug interactions, the geometric mean ratios and corresponding 90 percent (%) confidence interval (CI) of AUC(0-last) of parent probe drug before (Day 1) and after treatment with vemurafenib (Day 20) was calculated. Ratio and corresponding 90% CI of AUC(0-last) (Day 20/Day 1) for each of the 5 probe drugs is reported.
- Geometric Mean Ratio of Maximum Plasma Concentration (Cmax) of Probe Parent Drugs [Day 1, 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours]
To assess the potential for drug-drug interactions, the geometric mean ratios and corresponding 90% CI of Cmax of parent probe drug before (Day 1) and after treatment with vemurafenib (Day 20) was calculated. Ratio and corresponding 90% CI of Cmax (Day 20/Day 1) for each of the 5 probe drugs is reported.
- Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs [Day 1, 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for paraxanthine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120, dextrorphan 0.5, 1.5, 2, 12, 18, 48, OH-midazolam 0.08, 0.25, 0.5, 0.75, 2, 10, OH-omeprazole 0.5, 1.5, 2, 2.5, 12, 18 hours]
AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. To assess the potential for drug-drug interactions, the geometric mean ratios and corresponding 90% CI of AUC(0-last) and Cmax of metabolites of parent probe drug before (Day 1) and after treatment with vemurafenib (Day 20) was calculated. Ratio and corresponding 90% CI of AUC(0-last) and Cmax (Day 20/Day 1) for each of the 4 probe drug metabolites is reported (paraxanthine [caffeine metabolite], dextrorphan [dextromethorphan metabolite], OH-midazolam [midazolam metabolite], OH-omeprazole (omeprazole metabolite); S-warfarin does not have a metabolite).
- AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 [Day 1: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours]
AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. AUC(0-inf) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero extrapolated to infinity. Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin, as S-warfarin does not have a metabolite.
- AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 [Day 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours]
AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. AUC(0-inf) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero extrapolated to infinity. Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin, as S-warfarin does not have a metabolite.
- Area Under the Plasma Concentration-Time Curve From Time Zero to 8, 12, and 24 Hours (AUC[0-8], AUC[0-12], AUC[0-24]) of Vemurafenib [0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19]
Area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to 8, 12, and 24 hours (AUC[0-8], AUC[0-12], AUC[0-24], respectively).
- Cmax of Probe Parent Drugs and Their Metabolites on Day 1 [Day 1: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours]
Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite.
- Cmax of Probe Parent Drugs and Their Metabolites on Day 20 [Day 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours]
Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite.
- Cmax of Vemurafenib [0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19]
- Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 [Day 1: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours]
Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite.
- Tmax of Probe Parent Drugs and Their Metabolites on Day 20 [Day 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours]
Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite.
- Tmax of Vemurafenib [0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19]
- Trough Plasma Concentration (Cmin) of Vemurafenib [Before morning dose (0 hour) on Day 19]
- Apparent Elimination Half-Life in Plasma (t1/2) of Probe Parent Drugs and Their Metabolites on Day 1 [Day 1: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours]
Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite.
- t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 [Day 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours]
Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite.
- Apparent Plasma Clearance (CL/F) of Probe Parent Drugs on Day 1 [Day 1: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours]
Drug clearance was a quantitative measure of the rate at which a drug substance was removed from the body. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed.
- CL/F of Probe Parent Drugs on Day 20 [Day 20: 0, 1, 3, 4, 6, 8, 24 hours, additionally for caffeine 0.5, 1.5, 2, 12, 18, 48, 72, 96, 120,dextromethorphan 0.5, 1.5, 2, 12, 18, 48,midazolam 0.08, 0.25, 0.5, 0.75, 2, 10,omeprazole 0.5, 1.5, 2, 2.5, 12, 18,S-warfarin 12, 48, 72, 96, 120 hours]
Drug clearance was a quantitative measure of the rate at which a drug substance was removed from the body. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed.
Secondary Outcome Measures
- Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) [Screening up to approximately 3.5 years (assessed at Screening, Day 1 of Cycle 3 thereafter Day 1 of every other cycle [every 2 months] and at end of study)]
Confirmed best overall response was defined as having best objective response as CR or PR, as assessed by investigator and confirmed at least 28 days after initial response, according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1). CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must decrease to normal (short axis less than [<] 10 millimeter [mm]). PR was defined as a 30% decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter. Percentage of participants with best overall response of CR or PR are reported.
- Duration of Response [Screening up to approximately 3.5 years (assessed at Screening, Day 1 of Cycle 3 thereafter Day 1 of every other cycle [every 2 months] and at end of study)]
Duration of response was defined as the time interval between the date of the earliest qualifying response and the date of disease progression (PD) or death, only for those participants whose best overall response was CR or PR, as assessed by investigator. CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must decrease to normal (short axis <10 mm). PR was defined as a 30% decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter. PD was defined as at least 20% increase in the sum of diameters of target lesions compared to Nadir (smallest sum of diameters on-study), unequivocal progression of existing non-target lesions, or presence of new lesion.
- Time to Response [Screening up to approximately 3.5 years (assessed at Screening, Day 1 of cycle 3 thereafter Day 1 of every other cycle [every 2 months] and at end of study)]
Time to response was defined as the interval between the date of the first treatment and the date of the first documentation of confirmed CR or PR (as assessed by investigator), whichever occurred first. CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must decrease to normal (short axis <10 mm). PR was defined as a 30% decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter.
- Progression-Free Survival (PFS) [Screening up to approximately 3.5 years (assessed at Screening, Day 1 of cycle 3 thereafter Day 1 of every other cycle [every 2 months] and at end of study)]
PFS was defined the time interval between the date of the first treatment and the date of progression or death from any cause, whichever occurred first. Deaths that occurred in participants without disease progression were to be considered to be a PFS event on the date of death. Participants who neither progressed nor died were to be censored on the date of the last evaluable tumor assessment prior to the data cutoff date. PD, as assessed by investigator, was defined as at least 20% increase in the sum of diameters of target lesions compared to Nadir (smallest sum of diameters on-study), unequivocal progression of existing non-target lesions, or presence of new lesion.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Adult patient >/= 18 years of age
-
Malignant melanoma (Stage IV, AJCC)
-
Patients who are treatment-naive or have received prior systemic treatments for metastatic melanoma. Time elapsed between previous treatment for metastatic disease and first administration of study drug must be at least 28 days
-
Positive tested for BRAF mutation
-
Patients must not be poor metabolizers of CYP450 enzymes 2C9, 2C19, or 2D6 as determined by genotyping
-
Measurable disease by RECIST criteria
-
Negative pregnancy test; for fertile men and women, effective contraception during treatment and for 6 months after completion
Exclusion Criteria:
-
Active CNS lesions on CT/MRI within 28 days prior to enrollment
-
History of known spinal cord compression, or carcinomatous meningitis
-
Severe cardiovascular disease within 6 months prior to study
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | UCLA - School of Medicine | Los Angeles | California | United States | 90095 |
| 2 | Massachusetts General Hospital;Hematology/ Oncology | Boston | Massachusetts | United States | 02114 |
| 3 | Beth Israel Deaconess Medical Center | Boston | Massachusetts | United States | 02215 |
| 4 | Vanderbilt-Ingram Cancer Ctr | Nashville | Tennessee | United States | 37232 |
| 5 | Texas Oncology-Baylor Sammons Cancer Center | Dallas | Texas | United States | 75246 |
Sponsors and Collaborators
- Hoffmann-La Roche
Investigators
- Study Director: Clinical Trials, Hoffmann-La Roche
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01001299
Other Study ID Numbers:
- NP22676
First Posted:
Oct 26, 2009
Last Update Posted:
Aug 15, 2017
Last Verified:
Jun 1, 2017
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | 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 |
|---|---|
| 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 |
Baseline Characteristics
| Arm/Group Title | Vemurafenib |
|---|---|
| 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 Participants | 25 |
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
52.0
(13.73)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
11
44%
|
| Male |
14
56%
|
Outcome Measures
| 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 |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|
| 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). |
| Measure Participants | 20 |
| Caffeine (n = 19) |
2.56
|
| Dextromethorphan (n = 20) |
1.47
|
| Midazolam (n = 20) |
0.61
|
| Omeprazole (n = 20) |
1.13
|
| S-warfarin (n = 20) |
1.18
|
| Title | Geometric Mean Ratio of Maximum Plasma Concentration (Cmax) of Probe Parent Drugs |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|
| 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). |
| Measure Participants | 20 |
| Caffeine (n = 19) |
1.05
|
| Dextromethorphan (n = 20) |
1.36
|
| Midazolam (n = 20) |
0.65
|
| Omeprazole (n = 20) |
1.17
|
| S-warfarin (n = 20) |
1.00
|
| Title | Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|
| 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). |
| Measure Participants | 20 |
| Paraxanthine - AUC(0-last) (n = 19) |
1.15
|
| Paraxanthine - Cmax (n = 19) |
0.60
|
| Dextrorphan - AUC(0-last) (n = 20) |
1.46
|
| Dextrorphan - Cmax (n = 20) |
1.21
|
| OH-Midazolam - AUC(0-last) (n = 20) |
1.34
|
| OH-Midazolam - Cmax (n = 20) |
1.23
|
| OH-Omeprazole - AUC(0-last) (n = 20) |
1.16
|
| OH-Omeprazole - Cmax (n = 20) |
1.01
|
| 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 |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|
| 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). |
| Measure Participants | 20 |
| 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)
|
| Title | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|
| 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). |
| Measure Participants | 20 |
| 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)
|
| 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 |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Primary PK analysis population. |
| Arm/Group Title | Vemurafenib |
|---|---|
| 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). |
| Measure Participants | 21 |
| AUC(0-8) |
422
(121)
|
| AUC(0-12) |
601
(170)
|
| AUC(0-24) |
1176
(368)
|
| Title | Cmax of Probe Parent Drugs and Their Metabolites on Day 1 |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|
| 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). |
| Measure Participants | 20 |
| 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)
|
| Title | Cmax of Probe Parent Drugs and Their Metabolites on Day 20 |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|
| 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). |
| Measure Participants | 20 |
| 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)
|
| Title | Cmax of Vemurafenib |
|---|---|
| Description | |
| Time Frame | 0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Primary PK analysis population. |
| Arm/Group Title | Vemurafenib |
|---|---|
| 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). |
| Measure Participants | 21 |
| Mean (Standard Deviation) [micrograms per milliliter (mcg/mL)] |
61.7
(17.2)
|
| Title | Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|
| 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). |
| Measure Participants | 20 |
| Caffeine - Tmax (n = 19) |
1.00
|
| Paraxanthine - Tmax (n = 19) |
8.00
|
| S-Warfarin - Tmax (n = 20) |
3.00
|
| Omeprazole - Tmax (n = 20) |
3.00
|
| OH-Omeprazole - Tmax (n = 20) |
3.00
|
| Dextromethorphan - Tmax (n = 20) |
1.50
|
| Dextrorphan - Tmax (n = 20) |
1.50
|
| Midazolam - Tmax (n = 20) |
0.50
|
| OH-Midazolam - Tmax (n = 20) |
0.50
|
| Title | Tmax of Probe Parent Drugs and Their Metabolites on Day 20 |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|
| 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). |
| Measure Participants | 20 |
| Caffeine - Tmax (n = 19) |
2.00
|
| Paraxanthine - Tmax (n = 19) |
24.00
|
| S-Warfarin - Tmax (n = 20) |
3.00
|
| Omeprazole - Tmax (n = 20) |
2.5
|
| OH-Omeprazole - Tmax (n = 20) |
3.00
|
| Dextromethorphan - Tmax (n = 20) |
1.50
|
| Dextrorphan - Tmax (n = 20) |
1.50
|
| Midazolam - Tmax (n = 20) |
0.50
|
| OH-Midazolam - Tmax (n = 20) |
0.50
|
| Title | Tmax of Vemurafenib |
|---|---|
| Description | |
| Time Frame | 0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Primary PK analysis population. |
| Arm/Group Title | Vemurafenib |
|---|---|
| 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). |
| Measure Participants | 21 |
| Median (Full Range) [hours] |
3.10
|
| Title | Trough Plasma Concentration (Cmin) of Vemurafenib |
|---|---|
| Description | |
| Time Frame | Before morning dose (0 hour) on Day 19 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Primary PK analysis population. Here, number of participants analyzed signifies participants with evaluable data for this outcome. |
| Arm/Group Title | Vemurafenib |
|---|---|
| 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). |
| Measure Participants | 20 |
| Mean (Standard Deviation) [mcg/mL] |
54.5
(18.55)
|
| Title | Apparent Elimination Half-Life in Plasma (t1/2) of Probe Parent Drugs and Their Metabolites on Day 1 |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome. |
| Arm/Group Title | Vemurafenib |
|---|---|
| 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). |
| Measure Participants | 20 |
| 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)
|
| Title | t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome. |
| Arm/Group Title | Vemurafenib |
|---|---|
| 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). |
| Measure Participants | 20 |
| 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)
|
| Title | Apparent Plasma Clearance (CL/F) of Probe Parent Drugs on Day 1 |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|
| 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). |
| Measure Participants | 20 |
| 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)
|
| Title | CL/F of Probe Parent Drugs on Day 20 |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|
| 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). |
| Measure Participants | 20 |
| 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)
|
| Title | Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) |
|---|---|
| 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) |
Outcome Measure Data
| 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 |
|---|---|
| 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). |
| Measure Participants | 25 |
| Number [percentage of participants] |
44
176%
|
| Title | Duration of Response |
|---|---|
| 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) |
Outcome Measure Data
| 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 |
|---|---|
| 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). |
| Measure Participants | 0 |
| Title | Time to Response |
|---|---|
| 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) |
Outcome Measure Data
| 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 |
|---|---|
| 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). |
| Measure Participants | 0 |
| Title | Progression-Free Survival (PFS) |
|---|---|
| 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) |
Outcome Measure Data
| 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 |
|---|---|
| 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). |
| Measure Participants | 0 |
Adverse Events
| Time Frame | Up to 28 days after the last dose of study drug (median treatment duration: 144 days) | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Vemurafenib | |
| 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 (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Vemurafenib | ||
| Affected / at Risk (%) | # Events | |
| Total | 12/25 (48%) | |
| Blood and lymphatic system disorders | ||
| Febrile neutropenia | 1/25 (4%) | |
| Eye disorders | ||
| Uveitis | 1/25 (4%) | |
| Gastrointestinal disorders | ||
| Gastrointestinal haemorrhage | 1/25 (4%) | |
| General disorders | ||
| Pyrexia | 1/25 (4%) | |
| Investigations | ||
| Blood alkaline phosphatase increased | 1/25 (4%) | |
| Metabolism and nutrition disorders | ||
| Dehydration | 1/25 (4%) | |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
| Squamous cell carcinoma of skin | 8/25 (32%) | |
| Basal cell carcinoma | 3/25 (12%) | |
| Keratoacanthoma | 1/25 (4%) | |
| Nervous system disorders | ||
| Cerebrovasular accident | 1/25 (4%) | |
Other (Not Including Serious) Adverse Events |
||
| Vemurafenib | ||
| Affected / at Risk (%) | # Events | |
| Total | 25/25 (100%) | |
| Blood and lymphatic system disorders | ||
| Anaemia | 7/25 (28%) | |
| Ear and labyrinth disorders | ||
| Ear pain | 2/25 (8%) | |
| Eye disorders | ||
| Conjunctivitis | 2/25 (8%) | |
| Dry eye | 5/25 (20%) | |
| Lacrimation increased | 2/25 (8%) | |
| Photophobia | 2/25 (8%) | |
| Gastrointestinal disorders | ||
| Abdominal pain | 2/25 (8%) | |
| Constipation | 2/25 (8%) | |
| Diarrhoea | 8/25 (32%) | |
| Nausea | 11/25 (44%) | |
| Vomiting | 5/25 (20%) | |
| General disorders | ||
| Chills | 4/25 (16%) | |
| Fatigue | 19/25 (76%) | |
| Influenza like illness | 2/25 (8%) | |
| Nodule | 2/25 (8%) | |
| Oedema peripheral | 7/25 (28%) | |
| Pyrexia | 7/25 (28%) | |
| Hepatobiliary disorders | ||
| Hyperbilirubinaemia | 2/25 (8%) | |
| Infections and infestations | ||
| Folliculitis | 2/25 (8%) | |
| Nasopharyngitis | 2/25 (8%) | |
| Oral candidiasis | 2/25 (8%) | |
| Upper respiratory tract infection | 3/25 (12%) | |
| Urinary tract infection | 2/25 (8%) | |
| Injury, poisoning and procedural complications | ||
| Sunburn | 4/25 (16%) | |
| Investigations | ||
| Blood alkaline phosphatase increased | 3/25 (12%) | |
| Blood bilirubin increased | 2/25 (8%) | |
| Blood cholesterol increased | 2/25 (8%) | |
| Blood creatinine increased | 3/25 (12%) | |
| Gamma-glutamyltransferase increased | 4/25 (16%) | |
| Liver function test abnormal | 2/25 (8%) | |
| Lymphocyte count decreased | 2/25 (8%) | |
| Weight decreased | 3/25 (12%) | |
| White blood cell count decreased | 3/25 (12%) | |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 4/25 (16%) | |
| Dehydration | 2/25 (8%) | |
| Hypercholesterolaemia | 2/25 (8%) | |
| Hyperglycaemia | 2/25 (8%) | |
| Hyperuricaemia | 2/25 (8%) | |
| Hypokalaemia | 4/25 (16%) | |
| Hyponatraemia | 4/25 (16%) | |
| Hypophosphataemia | 2/25 (8%) | |
| Hypovolaemia | 2/25 (8%) | |
| Musculoskeletal and connective tissue disorders | ||
| Arthralgia | 18/25 (72%) | |
| Back pain | 2/25 (8%) | |
| Bursitis | 2/25 (8%) | |
| Joint stiffness | 3/25 (12%) | |
| Muscle spasms | 3/25 (12%) | |
| Musculoskeletal pain | 3/25 (12%) | |
| Pain in extremity | 8/25 (32%) | |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
| Acrochordon | 2/25 (8%) | |
| Skin papilloma | 9/25 (36%) | |
| Nervous system disorders | ||
| Dysgeusia | 4/25 (16%) | |
| Headache | 10/25 (40%) | |
| Hyperaesthesia | 2/25 (8%) | |
| Neuropathy peripheral | 2/25 (8%) | |
| Psychiatric disorders | ||
| Anxiety | 3/25 (12%) | |
| Insomnia | 3/25 (12%) | |
| Renal and urinary disorders | ||
| Dysuria | 2/25 (8%) | |
| Renal failure acute | 2/25 (8%) | |
| Reproductive system and breast disorders | ||
| Gynaecomastia | 3/25 (12%) | |
| Nipple swelling | 7/25 (28%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 3/25 (12%) | |
| Upper-airway cough syndrome | 2/25 (8%) | |
| Skin and subcutaneous tissue disorders | ||
| Acne | 4/25 (16%) | |
| Actinic Keratosis | 9/25 (36%) | |
| Blister | 2/25 (8%) | |
| Alopecia | 12/25 (48%) | |
| Dermal cyst | 2/25 (8%) | |
| Dermatitis acneiform | 2/25 (8%) | |
| Dry skin | 3/25 (12%) | |
| Erythema | 2/25 (8%) | |
| Hyperkeratosis | 13/25 (52%) | |
| Palmar-plantar erythrodysaesthesia syndrome | 4/25 (16%) | |
| Photosensitivity reaction | 15/25 (60%) | |
| Pruritus | 13/25 (52%) | |
| Rash | 7/25 (28%) | |
| Rash maculo-papular | 13/25 (52%) | |
| Skin lesion | 2/25 (8%) | |
| Vascular disorders | ||
| Hypertension | 4/25 (16%) | |
Limitations/Caveats
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).
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
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
| Name/Title | Medical Communications |
|---|---|
| Organization | Hoffmann-La Roche |
| Phone | 800-821-8590 |
| genentech@druginfo.com |
Responsible Party:
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01001299
Other Study ID Numbers:
- NP22676
First Posted:
Oct 26, 2009
Last Update Posted:
Aug 15, 2017
Last Verified:
Jun 1, 2017