An Open-Label, Randomized, Multicenter Trial of Encorafenib + Binimetinib Evaluating a Standard-dose and a High-dose Regimen in Patients With BRAFV600-mutant Melanoma Brain Metastasis (POLARIS)
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|ClinicalTrials.gov Identifier: NCT03911869|
Recruitment Status : Terminated (Study terminated due to lack of enrollment of the target population. There were no safety, efficacy, or regulatory interaction involved in the decision to stop enrollment.)
First Posted : April 11, 2019
Last Update Posted : April 25, 2022
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|Condition or disease||Intervention/treatment||Phase|
|Brain Metastases||Drug: encorafenib Drug: binimetinib||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||13 participants|
|Intervention Model:||Sequential Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 2, Open-Label, Randomized, Multicenter Trial of Encorafenib + Binimetinib Evaluating a Standard-dose and a High-dose Regimen in Patients With BRAFV600-Mutant Melanoma Brain Metastasis|
|Actual Study Start Date :||May 7, 2019|
|Actual Primary Completion Date :||January 27, 2022|
|Actual Study Completion Date :||January 27, 2022|
Experimental: Standard Dose Arm
Patients in the standard-dose treatment arm will receive encorafenib and binimetinib in 28-day cycles.
Patients who are able to tolerate the standard dose during the first 4 weeks of treatment (Cycle 1) should be dose-escalated to 600 mg encorafenib QD plus 45 mg binimetinib BID provided they meet protocol-defined criteria.
Experimental: High Dose Arm
Patients in the high-dose treatment arm will receive encorafenib and binimetinib in 28-day cycles.
- Safety Lead-in: Incidence of dose-limiting toxicities (DLTs) [ Time Frame: Up to 28 days ]
- Safety Lead-in: Incidence and severity of adverse events (AEs) [ Time Frame: Up to 28 days ]
- Safety Lead-in: Incidence of dose modifications due to AEs [ Time Frame: Up to 28 days ]
- Safety Lead-in: Incidence of treatment discontinuations due to AEs [ Time Frame: Up to 28 days ]
- Phase 2: Brain metastasis response rate (BMRR) per modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST v1.1) [ Time Frame: Up to 24 months ]
- Extracranial response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) [ Time Frame: Up to 24 months ]
- Global response rate (brain metastasis response per mRECIST v1.1 and extracranial response per RECIST v1.1) [ Time Frame: Up to 24 months ]Global response rate is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) per Investigator assessment for brain metastasis and extracranial lesions according to mRECIST v1.1 and RECIST v1.1, respectively.
- Disease control rate (DCR) [ Time Frame: Up to 24 months ]
- Duration of Response (DOR) [ Time Frame: Up to 24 months ]
- Progression-free survival (PFS) [ Time Frame: Up to 24 months ]
- Brain metastasis response rate (BMRR) per mRECIST v1.1 for Safety Lead-in only [ Time Frame: Up to 24 months ]
- Overall survival (OS) [ Time Frame: Up to 24 months ]
- Incidence and severity of adverse events (AEs) [ Time Frame: Up to 24 months ]
- Pharmacokinetics (PK) of binimetinib and its metabolite [ Time Frame: Day 1 and Day 15 of Cycle 1 and Day 1 of Cycle 2 and Cycle 3; 28 day cycles ]Plasma concentrations of binimetinib
- Pharmacokinetics (PK) of encorafenib and its metabolite [ Time Frame: Day 1 and Day 15 of Cycle 1 and Day 1 of Cycle 2 and 3; 28 day cycles ]Plasma concentrations of encorafenib
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
Key Inclusion Criteria:
- Histologically confirmed diagnosis of cutaneous melanoma with metastases to the brain.
- Presence of B-RAF proto-oncogene, V600 mutant (BRAFV600) mutation in tumor tissue previously determined by a local PCR or NGS-based assay at any time prior to Screening or by a central laboratory during Screening.
- Must have at least 1 parenchymal brain lesion ≥ 0.5 cm and ≤ 4 cm, defined as a magnetic resonance imaging (MRI) contrast-enhancing lesion that may be accurately measured in at least 1 dimension. (Measurable intracranial lesions that have been previously irradiated and have not been shown to be progressing following irradiation should not be considered as target lesions).
Patients may have received the following prior therapies:
- Safety Lead-in, Phase 2 Randomized , Phase 2 Arm A Cohort 1: May have received prior local therapy for brain metastases including but not restricted to brain surgery, whole brain radiotherapy, stereotactic radiotherapy or stereotactic radiosurgery. Multiple local (brain) therapies or combinations of local therapies are allowed. For patients receiving local therapy to all brain lesions (including WBRT), progression of pre-existing lesions based on RECIST 1.1 (> 20% increase in longest diameter on baseline scan) or new measurable lesions are required. For patients receiving local therapy for some but not all lesions, disease progression based on RECIST 1.1 is not required as long as there are remaining brain lesions that are measurable and not previously treated.
- Phase 2 Arm A Cohort 2: Received no prior local therapy (e.g., brain surgery, craniotomy, SRS or SRT) for brain metastases.
- All patients (Safety Lead-In and Phase 2): May have received prior immunotherapy.
- All patients (Safety Lead-In and Phase 2): If receiving concomitant corticosteroids must be on a stable or decreasing dose for at least 2 weeks prior to first dose of study treatment (up to a total daily dose of 4mg of dexamethasone or equivalent).
- An Eastern Cooperation Oncology Group Performance Status (ECOG PS) of 0 or 1 and Karnofsky score ≥ 80
- Adequate bone marrow, organ function and laboratory parameters
Key Exclusion Criteria:
- Patients with symptomatic brain metastasis.
- Uveal or mucosal melanoma.
- History of or current leptomeningeal metastases.
- Treatment with SRS or craniotomy within 14 days prior to start of study treatment, or treatment with whole-brain radiation within 28 days prior to study treatment. Patients who received local therapy should have complete recovery with no neurological sequelae.
Either of the following:
- Radiation therapy to non-brain visceral metastasis within 2 weeks prior to start of study treatment;
- Continuous or intermittent small-molecule therapeutics or investigational agents within 5 half-lives of the agent (or within 4 weeks prior to start of study treatment, when half-life is unknown).
- Patients treated in the adjuvant setting with BRAF or MEK inhibitor(s) < 6 months prior to enrollment. Patients who received BRAF or MEK inhibitors in the metastatic setting are excluded.
- Patient has not recovered to ≤ Grade 1 from toxic effects of prior therapy before starting study treatment.
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): NCT03911869
|Study Director:||Pfizer CT.gov Call Center||Pfizer|
|Other Study ID Numbers:||
C4221006 ( Other Identifier: Alias Study Number )
2018-004555-21 ( EudraCT Number )
|First Posted:||April 11, 2019 Key Record Dates|
|Last Update Posted:||April 25, 2022|
|Last Verified:||April 2022|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Yes|
|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|
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Central Nervous System Diseases
Nervous System Diseases