Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Micronutrients

All Drugs and Chemicals

Central Nervous System Stimulants

Adjuvants, Anesthesia

Central Nervous System Depressants

Psychotropic Drugs

Anticoagulants

Gastrointestinal Agents

Coagulants

Analgesics

Antitussive Agents

Respiratory System Agents

Other Dietary Supplements

Vitamins

Caffeine

Midazolam

Warfarin

Omeprazole

Vitamin K

Levomethorphan

Dextromethorphan

Menadione

Menaquinone

Naphthoquinone

Phylloquinone

Drug cocktail (caffeine, warfarin + vitamin K, omeprazole, dextromethorphan, midazolam) orally once daily, day 1 and day 20

Drug cocktail

RO5185426

Clinical Trials

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.

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

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

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.

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.

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) 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 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).

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

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.

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 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 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.

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.

Hoffmann-La Roche

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).

Vemurafenib

Age, Continuous

Sex: Female, Male

Baseline analysis population included all enrolled participants.

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).

Medical Communications

Caffeine (n = 19)

Dextromethorphan (n = 20)

Midazolam (n = 20)

Omeprazole (n = 20)

S-warfarin (n = 20)

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.

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

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

Geometric Mean Ratio of Maximum Plasma Concentration (Cmax) of Probe Parent Drugs

Paraxanthine - AUC(0-last) (n = 19)

Paraxanthine - Cmax (n = 19)

Dextrorphan - AUC(0-last) (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)

Geometric Mean Ratio of AUC(0-last) and Cmax of Metabolites of Probe Parent Drugs

Caffeine - AUC(0-last) (n = 19)

Caffeine - AUC(0-inf) (n = 19)

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-inf) (n = 20)

Dextromethorphan - AUC(0-last) (n = 20)

Dextromethorphan - AUC(0-inf) (n = 20)

Dextrorphan - AUC(0-inf) (n = 20)

Midazolam - AUC(0-last) (n = 20)

Midazolam - AUC(0-inf) (n = 20)

OH-Midazolam - AUC(0-inf) (n = 20)

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) and AUC(0-inf) of Probe Parent Drugs and Their Metabolites on Day 20

AUC(0-8)

AUC(0-12)

AUC(0-24)

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

Caffeine - Cmax (n = 19)

S-Warfarin - Cmax (n = 20)

Omeprazole - Cmax (n = 20)

Dextromethorphan - Cmax (n = 20)

Midazolam - Cmax (n = 20)

Cmax of Probe Parent Drugs and Their Metabolites on Day 1

Cmax of Probe Parent Drugs and Their Metabolites on Day 20

Cmax of Vemurafenib

Caffeine - Tmax (n = 19)

Paraxanthine - Tmax (n = 19)

S-Warfarin - 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)

Time to Reach Maximum Plasma Concentration (Tmax) of Probe Parent Drugs and Their Metabolites on Day 1

Tmax of Probe Parent Drugs and Their Metabolites on Day 20

Tmax of Vemurafenib

Primary PK analysis population. Here, number of participants analyzed signifies participants with evaluable data for this outcome.

Trough Plasma Concentration (Cmin) of Vemurafenib

Caffeine - t1/2

Paraxanthine - t1/2

S-Warfarin - t1/2

Omeprazole - t1/2

OH-Omeprazole - t1/2

Dextromethorphan - t1/2

Dextrorphan - t1/2

Midazolam - t1/2

OH-Midazolam - t1/2

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

Apparent Elimination Half-Life in Plasma (t1/2) of Probe Parent Drugs and Their Metabolites on Day 1

t1/2 of Probe Parent Drugs and Their Metabolites on Day 20

Caffeine - CL/F (n = 19)

S-Warfarin - CL/F (n = 20)

Omeprazole - CL/F (n = 20)

Dextromethorphan - CL/F (n = 20)

Midazolam - CL/F (n = 20)

Apparent Plasma Clearance (CL/F) of Probe Parent Drugs on Day 1

CL/F of Probe Parent Drugs on Day 20

Efficacy population included all enrolled participants who received any vemurafenib and had at least one post-baseline tumor assessment.

Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR)

The data for this outcome measure was not collected as the outcome was removed as per changes in planned analysis (protocol amendment).

Duration of Response

Time to Response

Progression-Free Survival (PFS)

Single oral doses of 5 probe drugs (caffeine 200 milligrams \[mg\] tablet, warfarin 10 mg tablet \[with Vitamin K 10 mg {2\*5 mg tablets}\], omeprazole 40 mg capsule, dextromethorphan 30 mg syrup, and midazolam 0.075 milligrams per kilogram \[mg/kg\] syrup) on Day 1, followed by 5-day washout. Vemurafenib (RO5185426) 960 mg (4\*240 mg film-coated tablets) orally twice daily on Day 6 to Day 19. Single oral doses of 5 probe drugs co-administered with vemurafenib 960 mg on Day 20, followed by vemurafenib 960 mg orally twice daily up to Day 28 and then vemurafenib 960 mg orally twice daily continuously in 28-day cycles until disease progression, toxicity, withdrawal of consent, loss to follow-up, or death (whichever occurred first).

Overall Study

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Prostatic Neoplasms

Prostatic Neoplasms, Castration-Resistant

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Lipid Regulating Agents

Hypoglycemic Agents

Anti-Allergic Agents

Bone Density Conservation Agents

Rosuvastatin Calcium

Pioglitazone

Fexofenadine

Calcium

Calcium, Dietary

Anticholesteremic Agents

Hypolipidemic Agents

Antimetabolites

Hydroxymethylglutaryl-CoA Reductase Inhibitors

Enzyme Inhibitors

Participants will receive drug cocktail (comprising of midazolam \[2 milligram {mg}\], warfarin \[10 mg\], vitamin K (10 mg), omeprazole (40 mg), and fexofenadine \[30 mg\]) orally on Study Day 1 and 43 (Cycle 2 Day 1). On Study Day 8 and 50, pioglitazone 15 mg will be administered orally and on Study Day 9 and 51, rosuvastatin 10 mg will be administered orally. JNJ 56021927, 240 mg once daily will be administered on Study Day 15 up to disease progression, unacceptable toxicity, withdrawal of consent, lost to follow-up, the participant is no longer receiving clinical benefit in the opinion of the Investigator, the start of subsequent anticancer therapy, or the Sponsor ends the study.

JNJ 56021927 will be administered once daily orally in a dose of 240 mg from Study Day 15 up to disease progression, unacceptable toxicity, withdrawal of consent, lost to follow-up, the participant is no longer receiving clinical benefit in the opinion of the Investigator, the start of subsequent anticancer therapy, or the Sponsor ends the study.

JNJ 56021927

Drug cocktail comprise of midazolam (2 mg), warfarin (10 mg), vitamin K (10 mg), omeprazole (40 mg), and fexofenadine (30 mg) will be administered on Study Day 1 and 43.

Drug Cocktail

Pioglitazone 15 mg will be administered orally on Study Day 8 and 50.

Rosuvastatin 15 mg will be administered orally on Study Day 9 and 51.

Rosuvastatin

Study Contact

Janssen Research & Development, LLC Clinical Trial

The purpose of this study is to evaluate the effects of repeat dosing of JNJ-56021927 on the pharmacokinetics for single-dose multiple cytochrome P450 (CYP450) enzymes (CYP3A4, CYP2C9, CYP2C19, CYP2C8) and transporter (P-gp and BRCP) substrates in participants with castration-resistant prostate cancer (CRPC).

This is a Phase 1, multicenter, open-label study in participants with CRPC. The study will consist of a Screening Phase to determine eligibility, a Pretreatment Phase, a Treatment Phase, and a Follow-up Phase. The study is designed to estimate the magnitude of the effects of JNJ-56021927 on the pharmacokinetics of probe substrates. In vitro studies have indicated that JNJ-56021927 and its active metabolite JNJ-56142060 (M3) have the potential to affect multiple cytochrome P450 (CYP) enzymes (CYP3A4, CYP2C9, CYP2C19, and CYP2C8) and drug transporters proteins (P-glycoprotein \[P-gp\] and breast cancer resistance protein \[BRCP\]) via inhibition or induction. In human hepatocytes, JNJ 56021927 and JNJ-56142060 (M3) were found to be inducers of CYP3A4. The induction of CYP3A4 suggests that JNJ-56021927 and M3 will induce other CYP isozymes and drug transporters (eg, CYP2C and P-gp via activation of pregnane X receptor). The study is designed to confirm the in vivo significance of these non-clinical findings.

A Study to Evaluate the Effect of Multiple Doses of JNJ-56021927 on the Pharmacokinetics of Multiple Cytochrome P450 and Transporter Substrates in Participants With Castration-Resistant Prostate Cancer

Drug-drug Interaction Study to Evaluate the Effect of Multiple Doses of JNJ-56021927 on the Pharmacokinetics of Multiple Cytochrome P450 and Transporter Substrates in Subjects With Castration-Resistant Prostate Cancer

Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Cmax for Midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.

The AUC (0-last) is the area under the plasma concentration-time curve from time zero to last quantifiable time. AUC (0-last) for Midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.

The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant. AUC\[0-infinity\]) for Midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.

The Tmax is defined as actual sampling time to reach maximum observed analyte concentration. Tmax for Midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.

Lambda(z) is first-order elimination rate constant associated with the terminal portion of the curve, determined as the negative slope of the terminal log-linear phase of the drug concentration-time curve. Lambda\[z\]) for midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.

The elimination half-life (t1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z). t1/2 for Midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. CL/F for Midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Pharmacokinetic Study of RO5185426 in Combination With a Drug Cocktail in Patients With Metastatic Melanoma	NCT01001299	Malignant Melan...	Drug cocktail RO5185426	18 Years -	Hoffmann-La Roche
A Study to Evaluate the Effect of Multiple Doses of JNJ-56021927 on the Pharmacokinetics of Multiple Cytochrome P450 and Transporter Substrates in Participants With Castration-Resistant Prostate Cancer	NCT02592317	Prostatic Neopl...	JNJ 56021927 Drug Cocktail Pioglitazone Rosuvastatin	18 Years -	Aragon Pharmaceuticals, Inc.
A Study to Evaluate the Effect of Multiple Doses of JNJ-56021927 on the Pharmacokinetics of Multiple Cytochrome P450 and Transporter Substrates in Participants With Castration-Resistant Prostate Cancer	NCT02592317	Prostatic Neopl...	JNJ 56021927 Drug Cocktail Pioglitazone Rosuvastatin	18 Years -	Aragon Pharmaceuticals, Inc.
A Study of Abemaciclib in Participants With Cancer That is Advanced or Has Spread to Another Part(s) of the Body	NCT02688088	Neoplasm Metast...	Drug Cocktail Abemaciclib	18 Years -	Eli Lilly and Company

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