Clinical Trials /

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

NCT03864042

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pharmacokinetic Drug-drug Interaction Study of Encorafenib and Binimetinib on Probe Drugs in Patients With BRAF V600-mutant Melanoma or Other Advanced Solid Tumors
  • Official Title: An Open-label Phase 1 Study to Evaluate the Effects of Encorafenib in Combination With Binimetinib on the Pharmacokinetics of Losartan, Midazolam, Caffeine, Omeprazole, and Dextromethorphan Administered in a Cocktail Approach and on the Pharmacokinetics of Rosuvastatin in Patients With BRAF V600-mutant Unresectable or Metastatic Melanoma or Other Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: ARRAY-818-103
  • NCT ID: NCT03864042

Conditions

  • Advanced Solid Tumors
  • Metastatic Melanoma

Interventions

DrugSynonymsArms
losartanArm 1 - CYP Probe Cocktail
dextromethorphanArm 1 - CYP Probe Cocktail
caffeineArm 1 - CYP Probe Cocktail
omeprazoleArm 1 - CYP Probe Cocktail
midazolamArm 1 - CYP Probe Cocktail
rosuvastatinArm 2 - Rosuvastatin and Bupropion
bupropion immediate release (IR)Arm 2 - Rosuvastatin and Bupropion
encorafenibArm 1 - CYP Probe Cocktail
binimetinibArm 1 - CYP Probe Cocktail
modafinilArm 3 - Modafinil

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Arm 1 - CYP Probe CocktailExperimentalPatients 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 (2 x 15 mg) dextromethorphan oral capsule 100 mg caffeine 20 mg/mL oral liquid 20 mg omeprazole oral capsule 2 mg midazolam 2 mg/mL 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.
  • losartan
  • dextromethorphan
  • caffeine
  • omeprazole
  • midazolam
  • encorafenib
  • binimetinib
Arm 2 - Rosuvastatin and BupropionExperimentalPatients 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.
  • rosuvastatin
  • bupropion immediate release (IR)
  • encorafenib
  • binimetinib
Arm 3 - ModafinilExperimentalPatients 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 (2 × 200 mg) modafinil tablet once daily (QD)
  • encorafenib
  • binimetinib
  • modafinil

Eligibility 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;
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Probe substrate peak plasma concentration (Cmax) in Arms 1 and 2
Time Frame:multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Metabolite ratio (MRAUC) for 1-OH midazolam/midazolam, paraxanthine/caffeine, 5-hydroxy omeprazole/omeprazole, hydroxybupropion/bupropion and LHY746/encorafenib
Time Frame:multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:Metabolite ratio (MRCmax) for 1-OH midazolam/midazolam, paraxanthine/caffeine, 5-hydroxy omeprazole/omeprazole, hydroxybupropion/bupropion and LHY746/encorafenib
Time Frame:multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:Metabolite ration (MRAe0-8) for E-3174/losartan and dextrorphan/dextromethorphan
Time Frame:multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (time to reach Cmax [Tmax]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion
Time Frame:multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure: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
Time Frame:multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure: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
Time Frame:multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure: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
Time Frame:multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure: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
Time Frame:multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure: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
Time Frame:multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure: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
Time Frame:multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (urine concentration [Curine]) for losartan, E-3174, dextromethorphan and dextrorphan
Time Frame:multiple timepoints over 8 hours post dose on Day-7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (quantity of urine excreted during each collection interval) for losartan, E-3174, dextromethorphan and dextrorphan
Time Frame:multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (cumulative amount excreted in urine during each collection interval [CumA]e) for losartan, E-3174, dextromethorphan and dextrorphan
Time Frame:multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (percentage of dose recovered in urine [Fe] %) for losartan, E-3174, dextromethorphan and dextrorphan
Time Frame:multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (Cmax) for encorafenib, LHY746, binimetinib and AR00426032
Time Frame:multiple timepoints over 8 hours post dose on Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (AUClast) for encorafenib, LHY746, binimetinib and AR00426032
Time Frame:multiple timepoints over 8 hours post dose on Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (Tmax) for encorafenib, LHY746, binimetinib and AR00426032
Time Frame:multiple timepoints over 8 hours post dose on Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (AUCinf,) for encorafenib, LHY746, binimetinib and AR00426032
Time Frame:multiple timepoints over 8 hours post dose on Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (AUC%extrap) for encorafenib, LHY746, binimetinib and AR00426032
Time Frame:multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (Kel) for encorafenib, LHY746, binimetinib and AR00426032
Time Frame:multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (T1/2) for encorafenib, LHY746, binimetinib and AR00426032
Time Frame:multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (CL/F) for encorafenib, LHY746, binimetinib and AR00426032
Time Frame:multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (Vz/F) for encorafenib, LHY746, binimetinib and AR00426032
Time Frame:multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (Cmax) for encorafenib, LHY746, binimetinib and AR00426032
Time Frame:multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (AUClast) for encorafenib, LHY746, binimetinib and AR00426032
Time Frame:multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (Tmax) for encorafenib, LHY746, binimetinib and AR00426032
Time Frame:multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (AUCinf,) for encorafenib, LHY746, binimetinib and AR00426032
Time Frame:multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (AUC%extrap) for encorafenib, LHY746, binimetinib and AR00426032
Time Frame:multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (Kel) for encorafenib, LHY746, binimetinib and AR00426032
Time Frame:multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (CL/F) for encorafenib, LHY746, binimetinib and AR00426032
Time Frame:multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (T1/2) for encorafenib, LHY746, binimetinib and AR00426032
Time Frame:multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:PK parameter (Vz/F) for encorafenib, LHY746, binimetinib and AR00426032
Time Frame:multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)
Safety Issue:
Description:
Measure:Safety will be evaluated by monitoring adverse events (AEs)
Time Frame:From first dose of study intervention/treatment until the end of DDI phase (through 28 days)
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Array BioPharma

Trial Keywords

  • solid tumor
  • melanoma

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