Pharmacokinetic Drug-drug Interaction Study of Encorafenib and Binimetinib on Probe Drugs in Patients With BRAF V600-mutant Melanoma or Other Advanced Solid Tumours

Official Title

An Open-label Phase 1 Study to Evaluate Drug-Drug Interactions of Agents Co-Administered With Encorafenib and Binimetinib in Patients With BRAF V600-mutant Unresectable or Metastatic Melanoma or Other Advanced Solid Tumours

Summary:

This is an open-label, 3-arm, fixed-sequence study to evaluate the effect of single and multiple oral doses of encorafenib in combination with binimetinib on the single oral dose pharmacokinetics (PK) of cytochrome P450 (CYP) enzyme probe substrates using a probe cocktail, on an organic anion-transporting polypeptide/breast cancer resistance protein (OATP/BCRP) substrate using rosuvastatin and on a CYP2B6 substrate using bupropion. The effect of multiple oral doses of the moderate cytochrome P450 (CYP) inhibitor modafinil on encorafenib in combination with binimetinib will also be assessed. The study will have 2 treatment phases, a drug-drug interaction (DDI) phase followed by a post-DDI phase.

Trial Description

Primary Outcome:

• Probe substrate peak plasma concentration (Cmax) in Arms 1 and 2
• Probe substrate concentration from time zero to the time of last quantifiable concentration (AUClast) in Arms 1 and 2
• Changes in the amount of probe eliminated via urine over an 8-hour period (Ae0-8) in Arm 1
• Changes in plasma encorafenib and LHY746 Cmax and area under the concentration time curve (AUC) in Arm 3.

• Metabolite ratio (MRAUC) for 1-OH midazolam/midazolam, paraxanthine/caffeine, 5-hydroxy omeprazole/omeprazole, hydroxybupropion/bupropion and LHY746/encorafenib
• Metabolite ratio (MRCmax) for 1-OH midazolam/midazolam, paraxanthine/caffeine, 5-hydroxy omeprazole/omeprazole, hydroxybupropion/bupropion and LHY746/encorafenib
• Metabolite ration (MRAe0-8) for E-3174/losartan and dextrorphan/dextromethorphan
• PK parameter (time to reach Cmax [Tmax]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion
• PK parameter (AUC from time zero extrapolated to infinity [AUCinf]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion
• PK parameter (percent of AUC extrapolated [AUC%extrap]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion
• PK parameter (apparent terminal elimination half-life [T1/2]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion
• PK parameter (apparent terminal elimination rate constant [Kel]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion
• PK parameter (apparent total body clearance after extravascular administration [CL/F]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion
• PK parameter (apparent total volume of distribution after extravascular administration [Vz/F]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion
• PK parameter (urine concentration [Curine]) for losartan, E-3174, dextromethorphan and dextrorphan
• PK parameter (quantity of urine excreted during each collection interval) for losartan, E-3174, dextromethorphan and dextrorphan
• PK parameter (cumulative amount excreted in urine during each collection interval [CumA]e) for losartan, E-3174, dextromethorphan and dextrorphan
• PK parameter (percentage of dose recovered in urine [Fe] %) for losartan, E-3174, dextromethorphan and dextrorphan
• PK parameter (Cmax) for encorafenib, LHY746, binimetinib and AR00426032
• PK parameter (AUClast) for encorafenib, LHY746, binimetinib and AR00426032
• PK parameter (Tmax) for encorafenib, LHY746, binimetinib and AR00426032
• PK parameter (AUCinf,) for encorafenib, LHY746, binimetinib and AR00426032
• PK parameter (AUC%extrap) for encorafenib, LHY746, binimetinib and AR00426032
• PK parameter (Kel) for encorafenib, LHY746, binimetinib and AR00426032
• PK parameter (T1/2) for encorafenib, LHY746, binimetinib and AR00426032
• PK parameter (CL/F) for encorafenib, LHY746, binimetinib and AR00426032
• PK parameter (Vz/F) for encorafenib, LHY746, binimetinib and AR00426032
• PK parameter (Cmax) for encorafenib, LHY746, binimetinib and AR00426032
• PK parameter (AUClast) for encorafenib, LHY746, binimetinib and AR00426032
• PK parameter (Tmax) for encorafenib, LHY746, binimetinib and AR00426032
• PK parameter (AUCinf,) for encorafenib, LHY746, binimetinib and AR00426032
• PK parameter (AUC%extrap) for encorafenib, LHY746, binimetinib and AR00426032
• PK parameter (Kel) for encorafenib, LHY746, binimetinib and AR00426032
• PK parameter (CL/F) for encorafenib, LHY746, binimetinib and AR00426032
• PK parameter (T1/2) for encorafenib, LHY746, binimetinib and AR00426032
• PK parameter (Vz/F) for encorafenib, LHY746, binimetinib and AR00426032
• Safety will be evaluated by monitoring adverse events (AEs)

View this trial on ClinicalTrials.gov