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

NCT ID: NCT03864042

Last Updated: 2024-09-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 56 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-01-02
• Study Completion Date: 2023-05-29

Brief 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.

Conditions

Advanced Solid Tumors; Metastatic Melanoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

losartan

Intervention Type: DRUG

taken orally

dextromethorphan

Intervention Type: DRUG

taken orally

caffeine

Intervention Type: DRUG

taken orally

omeprazole

Intervention Type: DRUG

taken orally

midazolam

Intervention Type: DRUG

taken orally

encorafenib

Intervention Type: DRUG

taken orally

binimetinib

Intervention Type: DRUG

taken orally

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.

Group Type: EXPERIMENTAL

rosuvastatin

Intervention Type: DRUG

taken orally

bupropion immediate release (IR)

Intervention Type: DRUG

taken orally

encorafenib

Intervention Type: DRUG

taken orally

binimetinib

Intervention Type: DRUG

taken orally

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)

Group Type: EXPERIMENTAL

encorafenib

Intervention Type: DRUG

taken orally

binimetinib

Intervention Type: DRUG

taken orally

modafinil

Intervention Type: DRUG

taken orally

Interventions

losartan

taken orally

Intervention Type: DRUG

dextromethorphan

taken orally

Intervention Type: DRUG

caffeine

taken orally

Intervention Type: DRUG

omeprazole

taken orally

Intervention Type: DRUG

midazolam

taken orally

Intervention Type: DRUG

rosuvastatin

taken orally

Intervention Type: DRUG

bupropion immediate release (IR)

taken orally

Intervention Type: DRUG

encorafenib

taken orally

Intervention Type: DRUG

binimetinib

taken orally

Intervention Type: DRUG

modafinil

taken orally

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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.

Exclusion Criteria

• 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;

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pierre Fabre Laboratories

INDUSTRY

Sponsor Role: collaborator

Pfizer

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Pfizer CT.gov Call Center

Role: STUDY_DIRECTOR

Pfizer

Locations

UC Irvine Health

Orange, California, United States

University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)

Aurora, Colorado, United States

University of Illinois at Chicago

Chicago, Illinois, United States

Hopkins Eye Clinic

Hopkins, Minnesota, United States

Park Nicollet Eye Clinic

Maple Grove, Minnesota, United States

Regions Cancer Care Center

Saint Paul, Minnesota, United States

HealthPartners Specialty Center-Eye Care

Saint Paul, Minnesota, United States

Gabrail Cancer Center Research

Canton, Ohio, United States

University of TN Medical Center

Knoxville, Tennessee, United States

Mary Crowley Cancer Research - Medical City Hospital

Dallas, Texas, United States

Utah Cancer Specialists

West Valley City, Utah, United States

Universitair Ziekenhuis Antwerpen

Edegem, , Belgium

Cross Cancer Institute

Edmonton, Alberta, Canada

Princess Margaret Cancer Centre

Toronto, Ontario, Canada

Sir Mortimer B Davis Jewish General Hospital

Montreal, Quebec, Canada

McGill University Health Center

Montreal, Quebec, Canada

Jewish General Hospital

Montrea, Quebec, Canada

Het Nederlands Kanker Instituut Antoni Van Leeuwenhoek Ziekenhuis

Amsterdam, , Netherlands

Erasmus Medical Center

Rotterdam, , Netherlands

Hospital del Mar

Barcelona, , Spain

Hospital Clinico Universitario Virgen de la Arrixaca

El Palmar, , Spain

Hospital Universitari Arnau de Vilanova

Lleida, , Spain

Hospital Beata Maria Ana

Madrid, , Spain

Hospital General Universitario Gregorio Marañon

Madrid, , Spain

Clinica Rementeria

Madrid, , Spain

MD Anderson Cancer Center Madrid

Madrid, , Spain

Hospital Universitario HM Sanchinarro - CIOCC

Madrid, , Spain

CERCO

Seville, , Spain

Hospital Universitario Virgen Macarena

Seville, , Spain

Countries

United States; Belgium; Canada; Netherlands; Spain

References

Piscitelli J, Reddy MB, Wollenberg L, Del Frari L, Gong J, Matschke K, Williams JH. Evaluation of the effect of modafinil on the pharmacokinetics of encorafenib and binimetinib in patients with BRAF V600-mutant advanced solid tumors. Cancer Chemother Pharmacol. 2024 Sep;94(3):337-347. doi: 10.1007/s00280-024-04676-2. Epub 2024 Jun 15.

Reference Type: DERIVED

PMID: 38878209 (View on PubMed)

Piscitelli J, Reddy MB, Wollenberg L, Del Frari L, Gong J, Wood L, Zhang Y, Matschke K, Williams JH. Clinical Evaluation of the Effect of Encorafenib on Bupropion, Rosuvastatin, and Coproporphyrin I and Considerations for Statin Coadministration. Clin Pharmacokinet. 2024 Apr;63(4):483-496. doi: 10.1007/s40262-024-01352-9. Epub 2024 Feb 29.

Reference Type: DERIVED

PMID: 38424308 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://pmiform.com/clinical-trial-info-request?StudyID=ARRAY-818-103

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

Other Identifiers

C4221003

Identifier Type: OTHER

Identifier Source: secondary_id

2019-001036-66

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ARRAY-818-103

Identifier Type: -

Identifier Source: org_study_id