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

Pfizer

Status and phase: Completed; Phase 1

Conditions: Advanced Solid Tumors; Metastatic Melanoma

Treatments: Drug: midazolam; Drug: omeprazole; Drug: caffeine; Drug: bupropion immediate release (IR); Drug: encorafenib; Drug: dextromethorphan; Drug: binimetinib; Drug: modafinil; Drug: rosuvastatin; Drug: losartan

Study type: Interventional

Funder types: Industry

Identifiers

NCT03864042

C4221003 (Other Identifier)

ARRAY-818-103

2019-001036-66 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 56 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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;

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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56 participants in 3 patient groups

Arm 1 - CYP Probe Cocktail

Experimental group

Description:

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.

Treatment:

Drug: losartan

Drug: binimetinib

Drug: dextromethorphan

Drug: encorafenib

Drug: midazolam

Drug: omeprazole

Drug: caffeine

Arm 2 - Rosuvastatin and Bupropion

Experimental group

Description:

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.

Treatment:

Drug: rosuvastatin

Drug: binimetinib

Drug: encorafenib

Drug: bupropion immediate release (IR)

Arm 3 - Modafinil

Experimental group

Description:

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)

Treatment:

Drug: modafinil

Drug: binimetinib

Drug: encorafenib