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

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

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.

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumors; Metastatic Melanoma
• Intervention / Treatment: Drug: encorafenib; Drug: binimetinib; Drug: losartan; Drug: dextromethorphan; Drug: caffeine; Drug: omeprazole; Drug: midazolam; Drug: rosuvastatin; Drug: bupropion immediate release (IR); Drug: modafinil

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Edegem, Belgium, 2650
    • Universitair Ziekenhuis Antwerpen
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
  • Quebec
    • Montrea, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
    • Montreal, Quebec, Canada, H4A 3J1
      • McGill University Health Center
    • Montreal, Quebec, Canada, H3T 1E2
      • Sir Mortimer B Davis Jewish General Hospital
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Het Nederlands Kanker Instituut Antoni Van Leeuwenhoek Ziekenhuis
  • Rotterdam, Netherlands, 3000 CA
    • Erasmus Medical Center
• Spain
  • Barcelona, Spain, 08003
    • Hospital del Mar
  • El Palmar, Spain, 30120
    • Hospital Clinico Universitario Virgen de la Arrixaca
  • Lleida, Spain, 25198
    • Hospital Universitari Arnau de Vilanova
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon
  • Madrid, Spain, 28033
    • MD Anderson Cancer Center Madrid
  • Madrid, Spain, 28050
    • Hospital Universitario HM Sanchinarro - CIOCC
  • Madrid, Spain, 28010
    • Clinica Rementeria
  • Madrid, Spain, 28007
    • Hospital Beata Maria Ana
  • Sevilla, Spain, 41009
    • Hospital Universitario Virgen Macarena
  • Sevilla, Spain, 41009
    • CERCO
• United States
  • California
    • Orange, California, United States, 92868-3201
      • UC Irvine Health
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago
  • Minnesota
    • Hopkins, Minnesota, United States, 55343-8087
      • Hopkins Eye Clinic
    • Maple Grove, Minnesota, United States, 55369
      • Park Nicollet Eye Clinic
    • Saint Paul, Minnesota, United States, 55101
      • Regions Cancer Care Center
    • Saint Paul, Minnesota, United States, 55130
      • HealthPartners Specialty Center-Eye Care
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center Research
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • University of TN Medical Center
  • Texas
    • Dallas, Texas, United States, 75230
      • Mary Crowley Cancer Research - Medical City Hospital
  • Utah
    • West Valley City, Utah, United States, 84119
      • Utah Cancer Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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;

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1 - CYP Probe Cocktail; 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: encorafenib; taken orally; Drug: binimetinib; taken orally; Drug: losartan; taken orally; Drug: dextromethorphan; taken orally; Drug: caffeine; taken orally; Drug: omeprazole; taken orally; Drug: midazolam; taken orally
Experimental: Arm 2 - Rosuvastatin and Bupropion; 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: encorafenib; taken orally; Drug: binimetinib; taken orally; Drug: rosuvastatin; taken orally; Drug: bupropion immediate release (IR); taken orally
Experimental: Arm 3 - Modafinil; 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; taken orally; Drug: binimetinib; taken orally; Drug: modafinil; taken orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Concentration (Cmax) of Plasma Midazolam on Day -7, Day 1, and Day 14	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Paraxanthine on Day -7, Day 1, and Day 14	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Paraxanthine was the metabolite of caffeine.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Omeprazole on Day -7, Day 1, and Day 14	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma 5-OH Omeprazole on Day -7, Day 1, and Day 14	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. 5-OH Omeprazole was the metabolite of omeprazole.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Bupropion on Day -7, Day 1 and Day 14	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Hydroxybupropion was the metabolite of bupropion.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Area Under the Concentration-Time Profile From Time 0 to The Time of The Last Quantifiable Concentration (AUClast) of Plasma Midazolam on Day -7, Day 1, and Day 14	AUClast is area under the concentration-time profile (AUC) from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14	AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14	AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14	AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14	AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14	AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Paraxanthine on Day -7, Day 1, and Day 14	AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Paraxanthine was the metabolite of caffeine.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Omeprazole on Day -7, Day 1, and Day 14	AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma 5-OH Omeprazole in Arm 1 on Day -7, Day 1 and Day 14	AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. 5-OH Omeprazole was the metabolite of omeprazole.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Rosuvastatin on Day -7, Day 1 and Day 14	AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Bupropion on Day -7, Day 1 and Day 14	AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14	AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Hydroxybupropion was the metabolite of bupropion.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
The Amount Eliminated Via Urine Over an 8-Hour Period (Ae0-8) of Losartan on Day -7, Day 1 and Day 14	Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours.	0 to 8 hours after dosing on Days -7, 1 and 14
Ae0-8 of E-3174 on Day -7, Day 1 and Day 14	Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. E-3174 was the metabolite of losartan.	0 to 8 hours after dosing on Days -7, 1 and 14
Ae0-8 of Dextromethorphan on Day -7, Day 1 and Day 14	Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours.	0 to 8 hours after dosing on Days -7, 1 and 14
Ae0-8 of Dextrorphan on Day -7, Day 1 and Day 14	Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. Dextrorphan was the metabolite of dextromethorphan.	0 to 8 hours after dosing on Days -7, 1 and 14
Cmax of Plasma Encorafenib on Day 14 and Day 21 in Arm 3	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Cmax of Plasma LHY746 on Day 14 and Day 21 in Arm 3	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
AUClast of Plasma Encorafenib on Day 14 and Day 21 in Arm 3	AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
AUClast of Plasma LHY746 on Day 14 and Day 21 in Arm 3	AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. LHY746 was the metabolite of encorafenib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14	MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight (MW), which was calculated by [AUClast (metabolite) × MW (parent)] / [AUClast (parent) × MW (metabolite)]. 1-OH midazolam was the metabolite of midazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Ratio of AUC From Time Zero Extrapolated to Infinity (AUCinf) Values of the Metabolite Compared to Parent (MRAUCinf) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14	MRAUCinf is the ratio of AUCinf values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [AUCinf (metabolite) × MW (parent)] / [AUCinf (parent) × MW (metabolite)]. 1-OH midazolam was the metabolite of midazolam. AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
MRAUClast for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14	MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [AUClast (metabolite) × MW (parent)] / [AUClast (parent) × MW (metabolite)]. Paraxanthine was the metabolite of caffeine.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
MRAUClast for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14	MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [AUClast (metabolite) × MW (parent)] / [AUClast (parent) × MW (metabolite)]. 5-OH Omeprazole was the metabolite of omeprazole.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
MRAUCinf for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14	MRAUCinf is the ratio of AUCinf values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [AUCinf (metabolite) × MW (parent)] / [AUCinf (parent) × MW (metabolite)]. 5-OH Omeprazole was the metabolite of omeprazole. AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
MRAUClast for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14	MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [AUClast (metabolite) × MW (parent)] / [AUClast (parent) × MW (metabolite)]. Hydroxybupropion was the metabolite of bupropion.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
MRAUClast for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21	MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [AUClast (metabolite) × MW (parent)] / [AUClast (parent) × MW (metabolite)]. LHY746 was the metabolite of encorafenib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14	MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [Cmax (metabolite) × MW (parent)] / [Cmax (parent) × MW (metabolite)]. 1-OH midazolam was the metabolite of midazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
MRCmax for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14	MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [Cmax (metabolite) × MW (parent)] / [Cmax (parent) × MW (metabolite)]. Paraxanthine was the metabolite of caffeine.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
MRCmax for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14	MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [Cmax (metabolite) × MW (parent)] / [Cmax (parent) × MW (metabolite)]. 5-OH Omeprazole was the metabolite of omeprazole.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
MRCmax for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14	MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [Cmax (metabolite) × MW (parent)] / [Cmax (parent) × MW (metabolite)]. Hydroxybupropion was the metabolite of bupropion.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
MRCmax for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21	MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [Cmax (metabolite) × MW (parent)] / [Cmax (parent) × MW (metabolite)]. LHY746 was the metabolite of encorafenib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Ratio of Ae0-8 Values of the Metabolite Compared to Parent (MRAe0-8) for E-3174/Losartan on Day -7, Day 1 and Day 14	Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. MRAe0-8 is the ratio of Ae0-8 values of the metabolite compared to parent, corrected for molecular weight. E-3174 was the metabolite of losartan.	0 to 8 hours after dosing on Days -7, 1 and 14
MRAe0-8 for Dextrorphan/Dextromethorphan on Day -7, Day 1 and Day 14	Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. MRAe0-8 is the ratio of Ae0-8 values of the metabolite compared to parent, corrected for molecular weight. Dextrorphan was the metabolite of dextromethorphan.	0 to 8 hours after dosing on Days -7, 1 and 14
Time to Reach Cmax (Tmax) of Plasma Midazolam on Day -7, Day 1 and Day 14	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Tmax of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14.
Tmax of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Tmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Tmax of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Tmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Tmax of Plasma Paraxanthine on Day -7, Day 1 and Day 14	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Paraxanthine was the metabolite of caffeine.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Tmax of Plasma Omeprazole on Day -7, Day 1 and Day 14	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.	Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14
Tmax of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. 5-OH Omeprazole was the metabolite of omeprazole.	Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14
Tmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Tmax of Plasma Bupropion on Day -7, Day 1 and Day 14	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Tmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Hydroxybupropion was the metabolite of bupropion.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUCinf of Plasma Midazolam on Day -7, Day 1 and Day 14	AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUCinf of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14	AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUCinf of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14	AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUCinf of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14	AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUCinf of Plasma Omeprazole on Day -7, Day 1 and Day 14	AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUCinf of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14	AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. 5-OH Omeprazole was the metabolite of omeprazole.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUCinf of Plasma Rosuvastatin on Day -7, Day 1 and Day 14	AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUCinf of Plasma Bupropion on Day -7, Day 1 and Day 14	AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Percent of AUC Extrapolated (AUC%Extrap) of Plasma Midazolam on Day -7, Day 1 and Day 14	AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUC%Extrap of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14	AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUC%Extrap of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14	AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUC%Extrap of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14	AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUC%Extrap of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14	AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUC%Extrap of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14	AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUC%Extrap of Plasma Omeprazole on Day -7, Day 1 and Day 14	AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUC%Extrap of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14	AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. 5-OH Omeprazole was the metabolite of omeprazole.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Apparent Terminal Elimination Rate Constant (Kel) of Plasma Midazolam on Day -7, Day 1 and Day 14	Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Kel of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14	Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Kel of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14	Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Kel of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14	Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Kel of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14	Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Kel of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14	Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Kel of Plasma Omeprazole on Day -7, Day 1 and Day 14	Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Kel of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14	Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. 5-OH Omeprazole was the metabolite of omeprazole.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Terminal Elimination Half-Life (T1/2) of Plasma Midazolam on Day -7, Day 1 and Day 14	T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14.
T1/2 of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14	T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
T1/2 of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14	T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
T1/2 of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14	T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14.
T1/2 of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14	T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
T1/2 of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14	T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
T1/2 of Plasma Omeprazole on Day -7, Day 1 and Day 14	T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
T1/2 of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14	T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. 5-OH Omeprazole was the metabolite of omeprazole.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
T1/2 of Plasma Rosuvastatin on Day -7, Day 1 and Day 14	T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
T1/2 of Plasma Bupropion on Day -7, Day 1 and Day 14	T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Apparent Clearance (CL/F) of Plasma Midazolam on Day -7, Day 1 and Day 14	CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14).	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
CL/F of Plasma Omeprazole on Day -7, Day 1 and Day 14	CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14).	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Apparent Total Volume of Distribution Following Oral Administration (Vz/F) of Plasma Midazolam on Day -7, Day 1 and Day 14	Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Vz/F of Plasma Omeprazole on Day -7, Day 1 and Day 14	Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Percentage of Dose Recovered in Urine (Fe) for Losartan on Day -7, Day 1 and Day 14	Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100.	Predose, and 0 to 8 hours postdose on Day -7, Day 1 and Day 14
Fe for E-3174 on Day -7, Day 1 and Day 14	Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100. E-3174 was the metabolite of losartan.	0 to 8 hours postdose on Day -7, Day 1 and Day 14
Fe for Dextromethorphan on Day -7, Day 1 and Day 14	Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100.	0 to 8 hours postdose on Day -7, Day 1 and Day 14
Fe for Dextrorphan on Day -7, Day 1 and Day 14	Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100. Dextrorphan was the metabolite of dextromethorphan.	0 to 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Encorafenib on Day 1 and Day 14	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.
Cmax of LHY746 on Day 1 and Day 14	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
Cmax of Binimetinib on Day 1 and Day 14	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.
Cmax of AR00426032 on Day 1 and Day 14	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
AUClast of Encorafenib on Day 1 and Day 14	AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.
AUClast of LHY746 on Day 1 and Day 14	AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. LHY746 was the metabolite of encorafenib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
AUClast of Binimetinib on Day 1 and Day 14	AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
AUClast of AR00426032 on Day 1 and Day 14	AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. AR00426032 was the metabolite of binimetinib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
Tmax of Encorafenib on Day 1 and Day 14	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.
Tmax of LHY746 on Day 1 and Day 14	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.	Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14
Tmax of Binimetinib on Day 1 and Day 14	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.
Tmax of AR00426032 on Day 1 and Day 14	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
AUCinf of Encorafenib on Day 1	AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
AUCinf of Binimetinib on Day 1	AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.
AUCinf of AR00426032 on Day 1	AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
T1/2 of Encorafenib on Day 1 and Day 14	T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
T1/2 of LHY746 on Day 1 and Day 14	T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. LHY746 was the metabolite of encorafenib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
T1/2 of Binimetinib on Day 1 and Day 14	T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
T1/2 of AR00426032 on Day 1 and Day 14	T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. AR00426032 was the metabolite of binimetinib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
AUC%Extrap of Encorafenib on Day 1	AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
AUC%Extrap of LHY746 on Day 1	AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. LHY746 was the metabolite of encorafenib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
AUC%Extrap of Binimetinib on Day 1	AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
AUC%Extrap of AR00426032 on Day 1	AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. AR00426032 was the metabolite of binimetinib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
Kel of Encorafenib on Day 1	Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
Kel of LHY746 on Day 1	Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. LHY746 was the metabolite of encorafenib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
Kel of Binimetinib on Day 1	Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
Kel of AR00426032 on Day 1	Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. AR00426032 was the metabolite of binimetinib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
CL/F of Encorafenib on Day 1	CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14).	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.
CL/F of Binimetinib on Day 1	CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14).	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.
Vz/F of Encorafenib on Day 1	Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.
Vz/F of Binimetinib on Day 1	Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.
Cmax of Binimetinib on Day 14 and Day 21	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Cmax of AR00426032 on Day 14 and Day 21	Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
AUClast of Binimetinib on Day 14 and Day 21	AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
AUClast of AR00426032 on Day 14 and Day 21	AUClast is AUC from time 0 (pre-dose) to the time of the last quantifiable concentration. AR00426032 was the metabolite of binimetinib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Tmax of Encorafenib on Day 14 and Day 21	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Tmax of LHY746 on Day 14 and Day 21	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Tmax of Binimetinib on Day 14 and Day 21	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Tmax of AR00426032 on Day 14 and Day 21	Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
T1/2 of Encorafenib on Day 14 and Day 21	T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
T1/2 of LHY746 on Day 14 and Day 21	T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. LHY746 was the metabolite of encorafenib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
T1/2 of Binimetinib on Day 14 and Day 21	T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
T1/2 of AR00426032 on Day 14 and Day 21	T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. AR00426032 was the metabolite of binimetinib.	Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase	An adverse event (AE) was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those with initial onset or increasing in severity between the first dose of encorafenib/binimetinib and up to 30 days after treatment discontinuation. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. SAEs were adjudicated according to the investigator's assessment. Treatment-related AEs and SAEs were determined by the investigator.	After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase
Number of Participants With Laboratory Abnormalities in the DDI Phase	Laboratory parameters:hematology (hemoglobin,hematocrit,red blood cell [RBC],platelet,white blood cell count [WBC],neutrophils,eosinophils,monocytes, basophils, lymphocytes), chemistry (albumin, alkaline phosphatase, alanine aminotransferase, amylase, aspartate aminotransferase, bicarbonate, total bilirubin, blood urea nitrogen, calcium, chloride, creatine kinase, creatinine, glucose, lactate dehydrogenase, lipase, magnesium, inorganic phosphate, potassium, total protein, sodium, uric acid), urinalysis (appearance, color, specific gravity, pH, ketones, protein, glucose, blood, nitrates, leukocyte esterase, and urine microscopy results including WBC, RBC, bacteria, epithelial cells, and casts), coagulation (activated partial thromboplastin time, prothrombin time/international normalized ratio) and others. Clinically notable: worsening from baseline by at least 2 grades or to greater than or equal to (>=) Grade 3, by Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.	After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase
Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase	Vital signs (temperature, pulse rate [PR]), systolic blood pressure [SBP]), and diastolic blood pressure [DBP]) were obtained with participants following at least 5 minutes of supine rest. Categorical criteria were defined as DBP>=100 millimeters of mercury (mm Hg)/less than or equal to (<=) 50 mmHg with increase/decrease from baseline of >=15 mmHg; SBP: >=160 mmHg/<=90 mmHg with increase/decrease from baseline of >=20 mmHg; PR: >=120 beats per minute (bpm)/<=50 bpm with increase/decrease from baseline of >=15 bpm; temperature for Arms 1 and 3: >=37.5°C/<=35°C; Arms 2: >=37.5°C/<=36°C.	After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase
Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase	Triplicate 12-lead ECG were performed after the participant had rested quietly for at least 10 minutes in a supine position. ECG parameters included RR interval, PR interval, QRS complex, QT interval, corrected QT (QTc) interval, Bazett's correction QT (QTcB) interval, Heart Rate and Fridericia's correction (QTcF) interval. The criterion included: QTcF >450 - <=480 mesc, >480 - <=500 msec, >500 msec, increase from baseline >30 - <=60 msec and increase from baseline >60 msec. QT interval >450 - <=480 msec, >480 - <=500 msec, >500 msec, increase from baseline >30 - <=60 msec and increase from baseline >60 msec. Heart rate increase from baseline >25% and value >100 bpm and decrease from baseline >25% and value <60 bpm. PR interval increase from baseline >25% and value >200 msec. QRS interval increase from baseline >25% and value >110 msec. Any new post-baseline notable ECG findings in the DDI phase was collected and reported in this outcome measure.	After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase
Number of Participants With Left Ventricular Ejection Fraction (LVEF) Abnormalities in the DDI Phase	LVEF abnormalities are defined according to CTCAE grade version 4.03. Participants was considered as having a LVEF abnormality if the worst post-baseline value was Grade 2, 3, or 4 according to the following classification: Grade 0: Non-missing value below Grade 2; Grade 2: LVEF between 40% and 50% or absolute change from baseline between -10% and <-20%; Grade 3: LVEF between 20% and 39% or absolute change from baseline lower than or equal to -20%; Grade 4: LVEF lower than 20%.	After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase	An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those with initial onset or increasing in severity between the first dose of encorafenib/binimetinib and up to 30 days after treatment discontinuation. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. SAEs were adjudicated according to the investigator's assessment. Treatment-related AEs and SAEs were determined by the investigator. Any significant findings in the laboratory test, physical examinations, ophthalmic examinations, vital signs, ECG tests were captured as an AE.	After 1st dose of encorafenib/binimetinib on Day 1 up to 30 days after the post-DDI Phase

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Pierre Fabre Laboratories
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): January 2, 2018
• Primary Completion (Actual): July 11, 2022
• Study Completion (Actual): May 29, 2023

Study Registration Dates

• First Submitted: February 1, 2019
• First Submitted That Met QC Criteria: March 4, 2019
• First Posted (Actual): March 6, 2019

Study Record Updates

• Last Update Posted (Actual): September 27, 2024
• Last Update Submitted That Met QC Criteria: May 17, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: solid tumor; melanoma
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Purinergic Antagonists; Purinergic Agents; Antimetabolites; Gastrointestinal Agents; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Analgesics, Opioid; Narcotics; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Respiratory System Agents; Cytochrome P-450 Enzyme Inducers; Anti-Ulcer Agents; Proton Pump Inhibitors; Cytochrome P-450 CYP3A Inducers; Dopamine Uptake Inhibitors; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Antitussive Agents; Wakefulness-Promoting Agents; Midazolam; Bupropion; Rosuvastatin Calcium; Dextromethorphan; Losartan; Caffeine; Omeprazole; Modafinil; Levomethorphan
• Other Study ID Numbers: ARRAY-818-103; C4221003 (Other Identifier: Alias Study Number); 2019-001036-66 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No