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

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ClinicalTrials.gov Identifier: NCT03864042
Recruitment Status : Recruiting
First Posted : March 6, 2019
Last Update Posted : April 8, 2021
Sponsor:
Collaborator:
Pierre Fabre Laboratories
Information provided by (Responsible Party):
Pfizer

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.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Metastatic Melanoma Drug: losartan Drug: dextromethorphan Drug: caffeine Drug: omeprazole Drug: midazolam Drug: rosuvastatin Drug: bupropion immediate release (IR) Drug: encorafenib Drug: binimetinib Drug: modafinil Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : January 2, 2018
Estimated Primary Completion Date : August 4, 2021
Estimated Study Completion Date : August 4, 2022


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: losartan
taken orally

Drug: dextromethorphan
taken orally

Drug: caffeine
taken orally

Drug: omeprazole
taken orally

Drug: midazolam
taken orally

Drug: encorafenib
taken orally

Drug: binimetinib
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: rosuvastatin
taken orally

Drug: bupropion immediate release (IR)
taken orally

Drug: encorafenib
taken orally

Drug: binimetinib
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




Primary Outcome Measures :
  1. 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) ]
  2. Probe substrate concentration from time zero to the time of last quantifiable concentration (AUClast) 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) ]
  3. Changes in the amount of probe eliminated via urine over an 8-hour period (Ae0-8) in Arm 1 [ Time Frame: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase) ]
  4. Changes in plasma encorafenib and LHY746 Cmax and area under the concentration time curve (AUC) in Arm 3. [ Time Frame: multiple timepoints over 8 hours post dose on Day 15 and Day 21 (Drug-Drug Interaction (DDI) phase) ]

Secondary Outcome Measures :
  1. 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) ]
  2. 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) ]
  3. 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) ]
  4. 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) ]
  5. 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) ]
  6. 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) ]
  7. 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) ]
  8. 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) ]
  9. 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) ]
  10. 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) ]
  11. 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) ]
  12. 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) ]
  13. 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) ]
  14. 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) ]
  15. 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) ]
  16. 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) ]
  17. 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) ]
  18. 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) ]
  19. 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) ]
  20. 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) ]
  21. 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) ]
  22. 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) ]
  23. 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) ]
  24. 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) ]
  25. 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) ]
  26. 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) ]
  27. 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) ]
  28. 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) ]
  29. 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) ]
  30. 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) ]
  31. 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) ]
  32. 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) ]
  33. 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) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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;

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03864042


Contacts
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Contact: Pfizer Pfizer CT.gov Call Center 1-800-718-1021 ClinicalTrials.gov_Inquiries@pfizer.com

Locations
Show Show 34 study locations
Sponsors and Collaborators
Pfizer
Pierre Fabre Laboratories
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
Additional Information:
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT03864042    
Other Study ID Numbers: ARRAY-818-103
C4221003 ( Other Identifier: Alias Study Number )
2019-001036-66 ( EudraCT Number )
First Posted: March 6, 2019    Key Record Dates
Last Update Posted: April 8, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Pfizer:
solid tumor
melanoma
Additional relevant MeSH terms:
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Melanoma
Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Losartan
Midazolam
Dextromethorphan
Caffeine
Modafinil
Bupropion
Omeprazole
Rosuvastatin Calcium
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action