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

Study Overview
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Brief Summary
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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.

Official Title
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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 Tumors

Conditions
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Advanced Solid Tumors, Metastatic Melanoma

Intervention / Treatment
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* Drug: losartan
* Drug: dextromethorphan
* Drug: caffeine
* Drug: omeprazole
* Drug: midazolam
* Drug: rosuvastatin
* Drug: bupropion immediate release (IR)
* Drug: encorafenib
* Drug: binimetinib
* Drug: modafinil


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria - Patients must meet all of the inclusion criteria to be eligible for enrollment into the study: Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer (AJCC) Stage IIIB, IIIC or IV; or other BRAF V600-mutant advanced solid tumors Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, as determined using a local test; Evidence of measurable or non-measurable lesions Patient with unresectable locally advanced or metastatic melanoma who has received no prior treatment or progressed on or after prior systemic therapy; Note: Prior therapy with a BRAF proto-oncogene serine-threonine protein kinase (BRAF) inhibitor and/or a mitogen-activated protein (MAP) kinase (MEK) inhibitor is permitted except in the regimen immediately prior to study entry Patient with other (non-melanoma) BRAF V600E and/or V600K -mutant advanced solid tumors who has progressed on standard therapy or for whom there are no available standard therapies; Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted except in the regimen immediately prior to study entry Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 Adequate bone marrow, hepatic and renal function as specified in the protocol ARM 1 ONLY: Non-smoker who has not used nicotine containing products for at least 3 months prior to the first dose. Key Exclusion Criteria - Patients meeting any of the following criteria are not eligible for enrollment in the study: Symptomatic brain metastasis. Patients previously treated or untreated for these conditions that are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable, with imaging (e.g., magnetic resonance imaging [MRI] or computed tomography [CT] demonstrating no current evidence of progressive brain metastases at screening); Symptomatic or untreated leptomeningeal disease; History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); Clinically significant cardiac disease Known hyper-coagulability risks other than malignancy (e.g., Factor V Leiden syndrome); Thromboembolic event except catheter-related venous thrombosis ≤ 12 weeks prior to starting study treatment. Discontinuation of prior BRAF and/or MEK inhibitor treatment due to left ventricular dysfunction, pneumonitis/interstitial lung disease, or retinal vein occlusion; ARM 1 ONLY: Positive urine cotinine test at screening ARM 3 ONLY: History of psychosis, depression or mania; History of angioedema; History of mitral valve prolapse; History of left ventricular hypertrophy;

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 - CYP Probe Cocktail<br>Patients will receive a single oral dose of the CYP Probe Cocktail on Day -7, Day 1, and Day 14: 25 mg losartan oral tablet 30 mg dextromethorphan oral capsule 50 mg caffeine oral liquid 20 mg omeprazole oral capsule 2 mg midazolam oral syrup encorafenib/binimetinib continuous daily dosing starting Day 1: 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD) 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID) All drugs will be taken within 10 minutes. | Drug: losartan<br>* taken orally<br>Drug: dextromethorphan<br>* taken orally<br>Drug: caffeine<br>* taken orally<br>Drug: omeprazole<br>* taken orally<br>Drug: midazolam<br>* taken orally<br>Drug: encorafenib<br>* taken orally<br>Drug: binimetinib<br>* taken orally<br>|
| Experimental: Arm 2 - Rosuvastatin and Bupropion<br>Patients will receive a single oral dose of rosuvastatin and bupropion once on Day -7, Day 1 and Day 14: 10 mg rosuvastatin oral tablet 75 mg bupropion immediate release (IR) oral tablet encorafenib/binimetinib continuous daily dosing starting Day 1: 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD) 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID) All drugs will be taken within 10 minutes. | Drug: rosuvastatin<br>* taken orally<br>Drug: bupropion immediate release (IR)<br>* taken orally<br>Drug: encorafenib<br>* taken orally<br>Drug: binimetinib<br>* taken orally<br>|
| Experimental: Arm 3 - Modafinil<br>Patients will begin encorafenib/binimetinib continuous daily dosing starting Day 1: 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD) 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID) then receive continuous treatment of modafinil on Day 15 through Day 21: - 400 mg modafinil tablet once daily (QD) | Drug: encorafenib<br>* taken orally<br>Drug: binimetinib<br>* taken orally<br>Drug: modafinil<br>* taken orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probe substrate peak plasma concentration (Cmax) in Arms 1 and 2 |  | multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| Probe substrate concentration from time zero to the time of last quantifiable concentration (AUClast) in Arms 1 and 2 |  | multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| Changes in the amount of probe eliminated via urine over an 8-hour period (Ae0-8) in Arm 1 |  | multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| Changes in plasma encorafenib and LHY746 Cmax and area under the concentration time curve (AUC) in Arm 3. |  | multiple timepoints over 8 hours post dose on Day 15 and Day 21 (Drug-Drug Interaction (DDI) phase) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolite ratio (MRAUC) for 1-OH midazolam/midazolam, paraxanthine/caffeine, 5-hydroxy omeprazole/omeprazole, hydroxybupropion/bupropion and LHY746/encorafenib |  | multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| Metabolite ratio (MRCmax) for 1-OH midazolam/midazolam, paraxanthine/caffeine, 5-hydroxy omeprazole/omeprazole, hydroxybupropion/bupropion and LHY746/encorafenib |  | multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| Metabolite ration (MRAe0-8) for E-3174/losartan and dextrorphan/dextromethorphan |  | multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (time to reach Cmax [Tmax]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion |  | multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| 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 |  | multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| 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 |  | multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| 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 |  | multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| 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 |  | multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| 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 |  | multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| 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 |  | multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (urine concentration [Curine]) for losartan, E-3174, dextromethorphan and dextrorphan |  | multiple timepoints over 8 hours post dose on Day-7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (quantity of urine excreted during each collection interval) for losartan, E-3174, dextromethorphan and dextrorphan |  | multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (cumulative amount excreted in urine during each collection interval [CumA]e) for losartan, E-3174, dextromethorphan and dextrorphan |  | multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (percentage of dose recovered in urine [Fe] %) for losartan, E-3174, dextromethorphan and dextrorphan |  | multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (Cmax) for encorafenib, LHY746, binimetinib and AR00426032 |  | multiple timepoints over 8 hours post dose on Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (AUClast) for encorafenib, LHY746, binimetinib and AR00426032 |  | multiple timepoints over 8 hours post dose on Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (Tmax) for encorafenib, LHY746, binimetinib and AR00426032 |  | multiple timepoints over 8 hours post dose on Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (AUCinf,) for encorafenib, LHY746, binimetinib and AR00426032 |  | multiple timepoints over 8 hours post dose on Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (AUC%extrap) for encorafenib, LHY746, binimetinib and AR00426032 |  | multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (Kel) for encorafenib, LHY746, binimetinib and AR00426032 |  | multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (T1/2) for encorafenib, LHY746, binimetinib and AR00426032 |  | multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (CL/F) for encorafenib, LHY746, binimetinib and AR00426032 |  | multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (Vz/F) for encorafenib, LHY746, binimetinib and AR00426032 |  | multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (Cmax) for encorafenib, LHY746, binimetinib and AR00426032 |  | multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (AUClast) for encorafenib, LHY746, binimetinib and AR00426032 |  | multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (Tmax) for encorafenib, LHY746, binimetinib and AR00426032 |  | multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (AUCinf,) for encorafenib, LHY746, binimetinib and AR00426032 |  | multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (AUC%extrap) for encorafenib, LHY746, binimetinib and AR00426032 |  | multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (Kel) for encorafenib, LHY746, binimetinib and AR00426032 |  | multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (CL/F) for encorafenib, LHY746, binimetinib and AR00426032 |  | multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (T1/2) for encorafenib, LHY746, binimetinib and AR00426032 |  | multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase) | 
| PK parameter (Vz/F) for encorafenib, LHY746, binimetinib and AR00426032 |  | multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase) | 
| Safety will be evaluated by monitoring adverse events (AEs) |  | From first dose of study intervention/treatment until the end of DDI phase (through 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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solid tumor, melanoma