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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Single arm | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Drug cocktail | Drug | Drug cocktail (caffeine, warfarin + vitamin K, omeprazole, dextromethorphan, midazolam) orally once daily, day 1 and day 20 |
|
| Measure | Description | Time Frame |
|---|---|---|
| Geometric Mean Ratio of Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Observed Sampling Time (AUC[0-last]) of Probe Parent Drugs | AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. To assess the potential for drug-drug interactions, the geometric mean ratios and corresponding 90 percent (%) confidence interval (CI) of AUC(0-last) of parent probe drug before (Day 1) and after treatment with vemurafenib (Day 20) was calculated. Ratio and corresponding 90% CI of AUC(0-last) (Day 20/Day 1) for each of the 5 probe drugs is reported. | 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 |
| Geometric Mean Ratio of Maximum Plasma Concentration (Cmax) of Probe Parent Drugs | To assess the potential for drug-drug interactions, the geometric mean ratios and corresponding 90% CI of Cmax of parent probe drug before (Day 1) and after treatment with vemurafenib (Day 20) was calculated. Ratio and corresponding 90% CI of Cmax (Day 20/Day 1) for each of the 5 probe drugs is reported. | 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 |
| Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs | AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. To assess the potential for drug-drug interactions, the geometric mean ratios and corresponding 90% CI of AUC(0-last) and Cmax of metabolites of parent probe drug before (Day 1) and after treatment with vemurafenib (Day 20) was calculated. Ratio and corresponding 90% CI of AUC(0-last) and Cmax (Day 20/Day 1) for each of the 4 probe drug metabolites is reported (paraxanthine [caffeine metabolite], dextrorphan [dextromethorphan metabolite], OH-midazolam [midazolam metabolite], OH-omeprazole (omeprazole metabolite); S-warfarin does not have a metabolite). |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) | Confirmed best overall response was defined as having best objective response as CR or PR, as assessed by investigator and confirmed at least 28 days after initial response, according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1). CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must decrease to normal (short axis less than [<] 10 millimeter [mm]). PR was defined as a 30% decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter. Percentage of participants with best overall response of CR or PR are reported. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Clinical Trials | Hoffmann-La Roche | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UCLA - School of Medicine | Los Angeles | California | 90095 | United States | ||
| Massachusetts General Hospital;Hematology/ Oncology |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22256804 | Derived | Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, Flaherty KT, Chapman PB, Kim MJ, Hayward R, Martin M, Yang H, Wang Q, Hilton H, Hang JS, Noe J, Lambros M, Geyer F, Dhomen N, Niculescu-Duvaz I, Zambon A, Niculescu-Duvaz D, Preece N, Robert L, Otte NJ, Mok S, Kee D, Ma Y, Zhang C, Habets G, Burton EA, Wong B, Nguyen H, Kockx M, Andries L, Lestini B, Nolop KB, Lee RJ, Joe AK, Troy JL, Gonzalez R, Hutson TE, Puzanov I, Chmielowski B, Springer CJ, McArthur GA, Sosman JA, Lo RS, Ribas A, Marais R. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012 Jan 19;366(3):207-15. doi: 10.1056/NEJMoa1105358. |
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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).
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| ID | Title | Description |
|---|---|---|
| FG000 | Vemurafenib | Single oral doses of 5 probe drugs (caffeine 200 milligrams [mg] tablet, warfarin 10 mg tablet [with Vitamin K 10 mg {2*5 mg tablets}], omeprazole 40 mg capsule, dextromethorphan 30 mg syrup, and midazolam 0.075 milligrams per kilogram [mg/kg] syrup) on Day 1, followed by 5-day washout. Vemurafenib (RO5185426) 960 mg (4*240 mg film-coated tablets) orally twice daily on Day 6 to Day 19. Single oral doses of 5 probe drugs co-administered with vemurafenib 960 mg on Day 20, followed by vemurafenib 960 mg orally twice daily up to Day 28 and then vemurafenib 960 mg orally twice daily continuously in 28-day cycles until disease progression, toxicity, withdrawal of consent, loss to follow-up, or death (whichever occurred first). |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Baseline analysis population included all enrolled participants.
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| ID | Title | Description |
|---|---|---|
| BG000 | Vemurafenib | Single oral doses of 5 probe drugs (caffeine 200 mg tablet, warfarin 10 mg tablet [with Vitamin K 10 mg {2*5 mg tablets}], omeprazole 40 mg capsule, dextromethorphan 30 mg syrup, and midazolam 0.075 mg/kg syrup) on Day 1, followed by 5-day washout. Vemurafenib 960 mg (4*240 mg film-coated tablets) orally twice daily on Day 6 to Day 19. Single oral doses of 5 probe drugs co-administered with vemurafenib 960 mg on Day 20, followed by vemurafenib 960 mg orally twice daily up to Day 28 and then vemurafenib 960 mg orally twice daily continuously in 28-day cycles until disease progression, toxicity, withdrawal of consent, loss to follow-up, or death (whichever occurred first). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Geometric Mean Ratio of Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Observed Sampling Time (AUC[0-last]) of Probe Parent Drugs | AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. To assess the potential for drug-drug interactions, the geometric mean ratios and corresponding 90 percent (%) confidence interval (CI) of AUC(0-last) of parent probe drug before (Day 1) and after treatment with vemurafenib (Day 20) was calculated. Ratio and corresponding 90% CI of AUC(0-last) (Day 20/Day 1) for each of the 5 probe drugs is reported. | 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. | Posted | Geometric Mean | 90% Confidence Interval | ratio | 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 |
Up to 28 days after the last dose of study drug (median treatment duration: 144 days)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Vemurafenib | Single oral doses of 5 probe drugs (caffeine 200 mg tablet, warfarin 10 mg tablet [with Vitamin K 10 mg {2*5 mg tablets}], omeprazole 40 mg capsule, dextromethorphan 30 mg syrup, and midazolam 0.075 mg/kg syrup) on Day 1, followed by 5-day washout. Vemurafenib 960 mg (4*240 mg film-coated tablets) orally twice daily on Day 6 to Day 19. Single oral doses of 5 probe drugs co-administered with vemurafenib 960 mg on Day 20, followed by vemurafenib 960 mg orally twice daily up to Day 28 and then vemurafenib 960 mg orally twice daily continuously in 28-day cycles until disease progression, toxicity, withdrawal of consent, loss to follow-up, or death (whichever occurred first). |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Squamous cell carcinoma of skin | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 16.0 | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA 16.0 | Non-systematic Assessment |
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).
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Medical Communications | Hoffmann-La Roche | 800-821-8590 | genentech@druginfo.com |
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| ID | Term |
|---|---|
| D008545 | Melanoma |
| ID | Term |
|---|---|
| D018358 | Neuroendocrine Tumors |
| D017599 | Neuroectodermal Tumors |
| D009373 | Neoplasms, Germ Cell and Embryonal |
| D009370 | Neoplasms by Histologic Type |
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| RO5185426 | Drug | 960 mg orally twice daily |
|
| 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) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. AUC(0-inf) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero extrapolated to infinity. Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin, as S-warfarin does not have a metabolite. | 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) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. AUC(0-inf) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero extrapolated to infinity. Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin, as S-warfarin does not have a metabolite. | 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 |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 8, 12, and 24 Hours (AUC[0-8], AUC[0-12], AUC[0-24]) of Vemurafenib | Area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to 8, 12, and 24 hours (AUC[0-8], AUC[0-12], AUC[0-24], respectively). | 0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19 |
| Cmax of Probe Parent Drugs and Their Metabolites on Day 1 | Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite. | 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 |
| Cmax of Probe Parent Drugs and Their Metabolites on Day 20 | Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite. | 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 |
| 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 | Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite. | 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 |
| Tmax of Probe Parent Drugs and Their Metabolites on Day 20 | Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite. | 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 |
| 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 | Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite. | 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 |
| t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 | Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite. | 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 |
| Apparent Plasma Clearance (CL/F) of Probe Parent Drugs on Day 1 | Drug clearance was a quantitative measure of the rate at which a drug substance was removed from the body. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed. | 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 |
| CL/F of Probe Parent Drugs on Day 20 | Drug clearance was a quantitative measure of the rate at which a drug substance was removed from the body. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed. | 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 |
| 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 | 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. | 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 | 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. | 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) |
| Progression-Free Survival (PFS) | PFS was defined the time interval between the date of the first treatment and the date of progression or death from any cause, whichever occurred first. Deaths that occurred in participants without disease progression were to be considered to be a PFS event on the date of death. Participants who neither progressed nor died were to be censored on the date of the last evaluable tumor assessment prior to the data cutoff date. PD, as assessed by investigator, was defined as at least 20% increase in the sum of diameters of target lesions compared to Nadir (smallest sum of diameters on-study), unequivocal progression of existing non-target lesions, or presence of new lesion. | 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) |
| Boston |
| Massachusetts |
| 02114 |
| United States |
| Beth Israel Deaconess Medical Center | Boston | Massachusetts | 02215 | United States |
| Vanderbilt-Ingram Cancer Ctr | Nashville | Tennessee | 37232 | United States |
| Texas Oncology-Baylor Sammons Cancer Center | Dallas | Texas | 75246 | United States |
| Began Taking Commercially Available Drug |
|
| Withdrew Consent |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| ID | Title | Description |
|---|---|---|
| OG000 | Vemurafenib | Single oral doses of 5 probe drugs (caffeine 200 mg tablet, warfarin 10 mg tablet [with Vitamin K 10 mg {2*5 mg tablets}], omeprazole 40 mg capsule, dextromethorphan 30 mg syrup, and midazolam 0.075 mg/kg syrup) on Day 1, followed by 5-day washout. Vemurafenib 960 mg (4*240 mg film-coated tablets) orally twice daily on Day 6 to Day 19. Single oral doses of 5 probe drugs co-administered with vemurafenib 960 mg on Day 20, followed by vemurafenib 960 mg orally twice daily up to Day 28 and then vemurafenib 960 mg orally twice daily continuously in 28-day cycles until disease progression, toxicity, withdrawal of consent, loss to follow-up, or death (whichever occurred first). |
|
|
| Primary | Geometric Mean Ratio of Maximum Plasma Concentration (Cmax) of Probe Parent Drugs | To assess the potential for drug-drug interactions, the geometric mean ratios and corresponding 90% CI of Cmax of parent probe drug before (Day 1) and after treatment with vemurafenib (Day 20) was calculated. Ratio and corresponding 90% CI of Cmax (Day 20/Day 1) for each of the 5 probe drugs is reported. | Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category. | Posted | Geometric Mean | 90% Confidence Interval | ratio | 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 |
|
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|
| Primary | Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs | AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. To assess the potential for drug-drug interactions, the geometric mean ratios and corresponding 90% CI of AUC(0-last) and Cmax of metabolites of parent probe drug before (Day 1) and after treatment with vemurafenib (Day 20) was calculated. Ratio and corresponding 90% CI of AUC(0-last) and Cmax (Day 20/Day 1) for each of the 4 probe drug metabolites is reported (paraxanthine [caffeine metabolite], dextrorphan [dextromethorphan metabolite], OH-midazolam [midazolam metabolite], OH-omeprazole (omeprazole metabolite); S-warfarin does not have a metabolite). | Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category. | Posted | Geometric Mean | 90% Confidence Interval | ratio | 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 |
|
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| Primary | AUC(0-last) and Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of Probe Parent Drugs and Their Metabolites on Day 1 | AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. AUC(0-inf) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero extrapolated to infinity. Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin, as S-warfarin does not have a metabolite. | Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category. | Posted | Mean | Standard Deviation | nanograms*hour per milliliter (ng*hr/mL) | 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 |
|
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| Primary | AUC(0-last) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20 | AUC(0-last) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to the last observed sampling time. AUC(0-inf) was defined as the area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero extrapolated to infinity. Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin, as S-warfarin does not have a metabolite. | Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category. | Posted | Mean | Standard Deviation | ng*hr/mL | 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 |
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|
| Primary | Area Under the Plasma Concentration-Time Curve From Time Zero to 8, 12, and 24 Hours (AUC[0-8], AUC[0-12], AUC[0-24]) of Vemurafenib | Area under the plasma concentration-time curve calculated using the linear trapezoidal rule from time zero to 8, 12, and 24 hours (AUC[0-8], AUC[0-12], AUC[0-24], respectively). | Primary PK analysis population. | Posted | Mean | Standard Deviation | micrograms*hour/milliliter (mcg*h/mL) | 0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19 |
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|
|
| Primary | Cmax of Probe Parent Drugs and Their Metabolites on Day 1 | Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite. | Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category. | Posted | Mean | Standard Deviation | nanograms per milliliter (ng/mL) | 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 |
|
|
|
| Primary | Cmax of Probe Parent Drugs and Their Metabolites on Day 20 | Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite. | Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category. | Posted | Mean | Standard Deviation | ng/mL | 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 |
|
|
|
| Primary | Cmax of Vemurafenib | Primary PK analysis population. | Posted | Mean | Standard Deviation | micrograms per milliliter (mcg/mL) | 0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19 |
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|
| Primary | Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1 | Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite. | Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category. | Posted | Median | Full Range | hours | 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 |
|
|
|
| Primary | Tmax of Probe Parent Drugs and Their Metabolites on Day 20 | Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite. | Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category. | Posted | Median | Full Range | hours | 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 |
|
|
|
| Primary | Tmax of Vemurafenib | Primary PK analysis population. | Posted | Median | Full Range | hours | 0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19 |
|
|
|
| Primary | Trough Plasma Concentration (Cmin) of Vemurafenib | Primary PK analysis population. Here, number of participants analyzed signifies participants with evaluable data for this outcome. | Posted | Mean | Standard Deviation | mcg/mL | Before morning dose (0 hour) on Day 19 |
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|
| Primary | Apparent Elimination Half-Life in Plasma (t1/2) of Probe Parent Drugs and Their Metabolites on Day 1 | Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite. | Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome. | Posted | Mean | Standard Deviation | hours | 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 |
|
|
|
| Primary | t1/2 of Probe Parent Drugs and Their Metabolites on Day 20 | Timeframe reported for parent probe drug is also applicable for their metabolite except S-warfarin as S-warfarin does not have a metabolite. | Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome. | Posted | Mean | Standard Deviation | hours | 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 |
|
|
|
| Primary | Apparent Plasma Clearance (CL/F) of Probe Parent Drugs on Day 1 | Drug clearance was a quantitative measure of the rate at which a drug substance was removed from the body. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed. | Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category. | Posted | Mean | Standard Deviation | milliliters per hour (mL/h) | 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 |
|
|
|
| Primary | CL/F of Probe Parent Drugs on Day 20 | Drug clearance was a quantitative measure of the rate at which a drug substance was removed from the body. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed. | Primary PK analysis population. Number of Participants Analyzed = participants evaluable for this outcome and n = participants evaluable for specified category. | Posted | Mean | Standard Deviation | mL/h | 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 |
|
|
|
| Secondary | Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) | Confirmed best overall response was defined as having best objective response as CR or PR, as assessed by investigator and confirmed at least 28 days after initial response, according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1). CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must decrease to normal (short axis less than [<] 10 millimeter [mm]). PR was defined as a 30% decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter. Percentage of participants with best overall response of CR or PR are reported. | Efficacy population included all enrolled participants who received any vemurafenib and had at least one post-baseline tumor assessment. | Posted | Number | percentage of participants | 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) |
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| Secondary | Duration of Response | Duration of response was defined as the time interval between the date of the earliest qualifying response and the date of disease progression (PD) or death, only for those participants whose best overall response was CR or PR, as assessed by investigator. CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must decrease to normal (short axis <10 mm). PR was defined as a 30% decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter. PD was defined as at least 20% increase in the sum of diameters of target lesions compared to Nadir (smallest sum of diameters on-study), unequivocal progression of existing non-target lesions, or presence of new lesion. | The data for this outcome measure was not collected as the outcome was removed as per changes in planned analysis (protocol amendment). | Posted | 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) |
|
|
| Secondary | Time to Response | Time to response was defined as the interval between the date of the first treatment and the date of the first documentation of confirmed CR or PR (as assessed by investigator), whichever occurred first. CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must decrease to normal (short axis <10 mm). PR was defined as a 30% decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter. | The data for this outcome measure was not collected as the outcome was removed as per changes in planned analysis (protocol amendment). | Posted | 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) |
|
|
| Secondary | Progression-Free Survival (PFS) | PFS was defined the time interval between the date of the first treatment and the date of progression or death from any cause, whichever occurred first. Deaths that occurred in participants without disease progression were to be considered to be a PFS event on the date of death. Participants who neither progressed nor died were to be censored on the date of the last evaluable tumor assessment prior to the data cutoff date. PD, as assessed by investigator, was defined as at least 20% increase in the sum of diameters of target lesions compared to Nadir (smallest sum of diameters on-study), unequivocal progression of existing non-target lesions, or presence of new lesion. | The data for this outcome measure was not collected as the outcome was removed as per changes in planned analysis (protocol amendment). | Posted | 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) |
|
|
| 12 |
| 25 |
| 25 |
| 25 |
| Basal cell carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 16.0 | Non-systematic Assessment |
|
| Keratoacanthoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 16.0 | Non-systematic Assessment |
|
| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Uveitis | Eye disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Gastrointestinal haemorrhage | Gastrointestinal disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Blood alkaline phosphatase increased | Investigations | MedDRA 16.0 | Non-systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Cerebrovasular accident | Nervous system disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Ear pain | Ear and labyrinth disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Conjunctivitis | Eye disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Dry eye | Eye disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Lacrimation increased | Eye disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Photophobia | Eye disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Chills | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Fatigue | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Influenza like illness | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Nodule | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Hyperbilirubinaemia | Hepatobiliary disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Folliculitis | Infections and infestations | MedDRA 16.0 | Non-systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA 16.0 | Non-systematic Assessment |
|
| Oral candidiasis | Infections and infestations | MedDRA 16.0 | Non-systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA 16.0 | Non-systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA 16.0 | Non-systematic Assessment |
|
| Sunburn | Injury, poisoning and procedural complications | MedDRA 16.0 | Non-systematic Assessment |
|
| Blood alkaline phosphatase increased | Investigations | MedDRA 16.0 | Non-systematic Assessment |
|
| Blood bilirubin increased | Investigations | MedDRA 16.0 | Non-systematic Assessment |
|
| Blood cholesterol increased | Investigations | MedDRA 16.0 | Non-systematic Assessment |
|
| Blood creatinine increased | Investigations | MedDRA 16.0 | Non-systematic Assessment |
|
| Gamma-glutamyltransferase increased | Investigations | MedDRA 16.0 | Non-systematic Assessment |
|
| Liver function test abnormal | Investigations | MedDRA 16.0 | Non-systematic Assessment |
|
| Lymphocyte count decreased | Investigations | MedDRA 16.0 | Non-systematic Assessment |
|
| Weight decreased | Investigations | MedDRA 16.0 | Non-systematic Assessment |
|
| White blood cell count decreased | Investigations | MedDRA 16.0 | Non-systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Hypercholesterolaemia | Metabolism and nutrition disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Hyperuricaemia | Metabolism and nutrition disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Hypophosphataemia | Metabolism and nutrition disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Hypovolaemia | Metabolism and nutrition disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Bursitis | Musculoskeletal and connective tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Joint stiffness | Musculoskeletal and connective tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Acrochordon | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 16.0 | Non-systematic Assessment |
|
| Skin papilloma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 16.0 | Non-systematic Assessment |
|
| Dysgeusia | Nervous system disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Hyperaesthesia | Nervous system disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Neuropathy peripheral | Nervous system disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Anxiety | Psychiatric disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Dysuria | Renal and urinary disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Renal failure acute | Renal and urinary disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Gynaecomastia | Reproductive system and breast disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Nipple swelling | Reproductive system and breast disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Upper-airway cough syndrome | Respiratory, thoracic and mediastinal disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Acne | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Actinic Keratosis | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Blister | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Alopecia | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Dermal cyst | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Dermatitis acneiform | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Dry skin | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Erythema | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Hyperkeratosis | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Palmar-plantar erythrodysaesthesia syndrome | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Photosensitivity reaction | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Rash maculo-papular | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Skin lesion | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA 16.0 | Non-systematic Assessment |
|
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.
| D009369 | Neoplasms |
| D009380 | Neoplasms, Nerve Tissue |
| D018326 | Nevi and Melanomas |
| D012878 | Skin Neoplasms |
| D009371 | Neoplasms by Site |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| Title | Measurements |
|---|---|
|
| Omeprazole (n = 20) |
|
| S-warfarin (n = 20) |
|
|
| Dextrorphan - Cmax (n = 20) |
|
| OH-Midazolam - AUC(0-last) (n = 20) |
|
| OH-Midazolam - Cmax (n = 20) |
|
| OH-Omeprazole - AUC(0-last) (n = 20) |
|
| OH-Omeprazole - Cmax (n = 20) |
|
|
| Paraxanthine - AUC(0-inf) (n = 19) |
|
| S-Warfarin - AUC(0-last) (n = 20) |
|
| S-Warfarin - AUC(0-inf) (n = 20) |
|
| Omeprazole - AUC(0-last) (n = 20) |
|
| Omeprazole - AUC(0-inf) (n = 20) |
|
| OH-Omeprazole - AUC(0-last) (n = 20) |
|
| OH-Omeprazole - AUC(0-inf) (n = 20) |
|
| Dextromethorphan - AUC(0-last) (n = 20) |
|
| Dextromethorphan - AUC(0-inf) (n = 20) |
|
| Dextrorphan - AUC(0-last) (n = 20) |
|
| Dextrorphan - AUC(0-inf) (n = 20) |
|
| Midazolam - AUC(0-last) (n = 20) |
|
| Midazolam - AUC(0-inf) (n = 20) |
|
| OH-Midazolam - AUC(0-last) (n = 20) |
|
| OH-Midazolam - AUC(0-inf) (n = 20) |
|
|
| Paraxanthine - AUC(0-inf) (n = 19) |
|
| S-Warfarin - AUC(0-last) (n = 20) |
|
| S-Warfarin - AUC(0-inf) (n = 20) |
|
| Omeprazole - AUC(0-last) (n = 20) |
|
| Omeprazole - AUC(0-inf) (n = 20) |
|
| OH-Omeprazole - AUC(0-last) (n = 20) |
|
| OH-Omeprazole - AUC(0-inf) (n = 20) |
|
| Dextromethorphan - AUC(0-last) (n = 20) |
|
| Dextromethorphan - AUC(0-inf) (n = 20) |
|
| Dextrorphan - AUC(0-last) (n = 20) |
|
| Dextrorphan - AUC(0-inf) (n = 20) |
|
| Midazolam - AUC(0-last) (n = 20) |
|
| Midazolam - AUC(0-inf) (n = 20) |
|
| OH-Midazolam - AUC(0-last) (n = 20) |
|
| OH-Midazolam - AUC(0-inf) (n = 20) |
|
| Title | Measurements |
|---|---|
|
| Title | Measurements |
|---|---|
|
| Omeprazole - Cmax (n = 20) |
|
| OH-Omeprazole - Cmax (n = 20) |
|
| Dextromethorphan - Cmax (n = 20) |
|
| Dextrorphan - Cmax (n = 20) |
|
| Midazolam - Cmax (n = 20) |
|
| OH-Midazolam - Cmax (n = 20) |
|
| Title | Measurements |
|---|---|
|
| Omeprazole - Cmax (n = 20) |
|
| OH-Omeprazole - Cmax (n = 20) |
|
| Dextromethorphan - Cmax (n = 20) |
|
| Dextrorphan - Cmax (n = 20) |
|
| Midazolam - Cmax (n = 20) |
|
| OH-Midazolam - Cmax (n = 20) |
|
|
| Omeprazole - Tmax (n = 20) |
|
| OH-Omeprazole - Tmax (n = 20) |
|
| Dextromethorphan - Tmax (n = 20) |
|
| Dextrorphan - Tmax (n = 20) |
|
| Midazolam - Tmax (n = 20) |
|
| OH-Midazolam - Tmax (n = 20) |
|
|
| Omeprazole - Tmax (n = 20) |
|
| OH-Omeprazole - Tmax (n = 20) |
|
| Dextromethorphan - Tmax (n = 20) |
|
| Dextrorphan - Tmax (n = 20) |
|
| Midazolam - Tmax (n = 20) |
|
| OH-Midazolam - Tmax (n = 20) |
|
| Title | Measurements |
|---|---|
|
| Omeprazole - t1/2 |
|
| OH-Omeprazole - t1/2 |
|
| Dextromethorphan - t1/2 |
|
| Dextrorphan - t1/2 |
|
| Midazolam - t1/2 |
|
| OH-Midazolam - t1/2 |
|
| Title | Measurements |
|---|---|
|
| Omeprazole - t1/2 |
|
| OH-Omeprazole - t1/2 |
|
| Dextromethorphan - t1/2 |
|
| Dextrorphan - t1/2 |
|
| Midazolam - t1/2 |
|
| OH-Midazolam - t1/2 |
|
| Title | Measurements |
|---|---|
|
| Dextromethorphan - CL/F (n = 20) |
|
| Midazolam - CL/F (n = 20) |
|
| Title | Measurements |
|---|---|
|
| Dextromethorphan - CL/F (n = 20) |
|
| Midazolam - CL/F (n = 20) |
|