Trial record 1 of 6 for:
Encorafenib and Binimetinib in Patients with BRAF V600-mutant
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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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT03864042 |
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Recruitment Status :
Recruiting
First Posted : March 6, 2019
Last Update Posted : April 8, 2021
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Sponsor:
Pfizer
Collaborator:
Pierre Fabre Laboratories
Information provided by (Responsible Party):
Pfizer
- Study Details
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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 |
| 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 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Melanoma
| 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:
encorafenib/binimetinib continuous daily dosing starting Day 1:
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:
encorafenib/binimetinib continuous daily dosing starting Day 1:
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:
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 :
- 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) ]
- 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) ]
- 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) ]
- 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 :
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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) ]
- 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 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.
| 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
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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
| Contact: Pfizer Pfizer CT.gov Call Center | 1-800-718-1021 | ClinicalTrials.gov_Inquiries@pfizer.com |
Locations
Show 34 study locations
Sponsors and Collaborators
Pfizer
Pierre Fabre Laboratories
Investigators
| Study Director: | Pfizer CT.gov Call Center | Pfizer |
Additional Information:
| 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. |
| 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 |