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: Active, not recruiting
• 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
• 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 Clínico Universitario Virgen de la Arrixaca
  • Lleida, Spain, 25198
    • Hospital Universitari Arnau de Vilanova
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Maranon
  • Madrid, Spain, 28033
    • MD Anderson Cancer Center Madrid
  • Madrid, Spain, 28050
    • Hospital Universitario HM Sanchinarro - CIOCC
  • Madrid, Spain, 28010
    • Clínica Rementería
  • Madrid, Spain, 28007
    • Hospital Beata María 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	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	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)

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 (Estimated): June 30, 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): June 8, 2023
• Last Update Submitted That Met QC Criteria: June 6, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: solid tumor; melanoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Central Nervous System Depressants; Enzyme Inhibitors; 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; 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
• 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