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

Advanced Solid Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03864042
• Other study ID #: ARRAY-818-103
• Secondary ID: C42210032019-001
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: January 2, 2018
• Est. completion date: June 30, 2023

Study information

• Verified date: June 2023
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 56
• Est. completion date: June 30, 2023
• Est. primary completion date: July 11, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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;

Related Conditions & MeSH terms

• Advanced Solid Tumors
• Melanoma
• Metastatic Melanoma

Intervention

Drug:
• losartan
taken orally
• dextromethorphan
taken orally
• caffeine
taken orally
• omeprazole
taken orally
• midazolam
taken orally
• rosuvastatin
taken orally
• bupropion immediate release (IR)
taken orally
• encorafenib
taken orally
• binimetinib
taken orally
• modafinil
taken orally

Locations

Country	Name	City	State
Belgium	Universitair Ziekenhuis Antwerpen	Edegem
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	Jewish General Hospital	Montrea	Quebec
Canada	McGill University Health Center	Montreal	Quebec
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
Netherlands	Het Nederlands Kanker Instituut Antoni Van Leeuwenhoek Ziekenhuis	Amsterdam
Netherlands	Erasmus Medical Center	Rotterdam
Spain	Hospital del Mar	Barcelona
Spain	Hospital Clinico Universitario Virgen de la Arrixaca	El Palmar
Spain	Hospital Universitari Arnau de Vilanova	Lleida
Spain	Clinica Rementeria	Madrid
Spain	Hospital Beata Maria Ana	Madrid
Spain	Hospital General Universitario Gregorio Marañon	Madrid
Spain	Hospital Universitario HM Sanchinarro - CIOCC	Madrid
Spain	MD Anderson Cancer Center Madrid	Madrid
Spain	CERCO	Sevilla
Spain	Hospital Universitario Virgen Macarena	Sevilla
United States	University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)	Aurora	Colorado
United States	Gabrail Cancer Center Research	Canton	Ohio
United States	University of Illinois at Chicago	Chicago	Illinois
United States	Mary Crowley Cancer Research - Medical City Hospital	Dallas	Texas
United States	Hopkins Eye Clinic	Hopkins	Minnesota
United States	University of TN Medical Center	Knoxville	Tennessee
United States	Park Nicollet Eye Clinic	Maple Grove	Minnesota
United States	UC Irvine Health	Orange	California
United States	HealthPartners Specialty Center-Eye Care	Saint Paul	Minnesota
United States	Regions Cancer Care Center	Saint Paul	Minnesota
United States	Utah Cancer Specialists	West Valley City	Utah

Sponsors (2)

Lead Sponsor	Collaborator
Pfizer	Pierre Fabre Laboratories

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)

External Links

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