A Pharmacokinetic Study of RO5185426 in Combination With a Drug Cocktail in Patients With Metastatic Melanoma
- Conditions
- Malignant Melanoma
- Interventions
- Drug: Drug cocktailDrug: RO5185426
- Registration Number
- NCT01001299
- Lead Sponsor
- Hoffmann-La Roche
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 25
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Single arm Drug cocktail - Single arm RO5185426 -
- Primary Outcome Measures
Name Time Method 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 Vemurafenib 0, 0.5, 1, 2, 4, 8, 12, 13, 14, 16, 18, 24 hours on Day 19 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.
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.
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.
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
Name Time Method 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.
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.
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.
Trial Locations
- Locations (5)
UCLA - School of Medicine
🇺🇸Los Angeles, California, United States
Massachusetts General Hospital;Hematology/ Oncology
🇺🇸Boston, Massachusetts, United States
Texas Oncology-Baylor Sammons Cancer Center
🇺🇸Dallas, Texas, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
Vanderbilt-Ingram Cancer Ctr
🇺🇸Nashville, Tennessee, United States