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)

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

This is a multicenter, randomized open-label Phase 2 study to assess the safety, efficacy and pharmacokinetic (PK) of 2 dosing regimens of encorafenib + binimetinib combination in patients with BRAFV600-mutant melanoma with brain metastasis. Approximately 100 patients will be enrolled, including 9 patients in a Safety Lead-in of the high-dose treatment arm. After a Screening Period, treatment will be administered in 28-day cycles and will continue until disease progression, unacceptable toxicity, withdrawal of consent, start of subsequent anticancer therapy, death.

Study Overview

• Status: Terminated
• Conditions: Brain Metastases
• Intervention / Treatment: Drug: encorafenib; Drug: binimetinib

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Caba, Argentina, C1121ABE
    • Fundacion Cidea
  • Ciudad Autónoma DE Buenosaires
    • Buenos Aires, Ciudad Autónoma DE Buenosaires, Argentina, CP1426ANZ
      • Instituto Médico Especializado Alexander Fleming
  • Santa FE
    • Rosario, Santa FE, Argentina, S2000KZE
      • Instituto de Oncología de Rosario
• Australia
  • New South Wales
    • Crows Nest, New South Wales, Australia, 2065
      • Crows Nest Eye Surgery
    • North Sydney, New South Wales, Australia, 2060
      • Melanoma Institute Australia
    • Wollstonecraft, New South Wales, Australia, 2065
      • Mater Imaging
    • st Leonards, New South Wales, Australia, 2065
      • Royal north shore center hospital dermatology clinics
• Belgium
  • Antwerpen
    • Edegem, Antwerpen, Belgium, 2650
      • UZ Antwerpen
• Italy
  • Napoli, Italy, 80131
    • S.C. Cardiologia
  • Napoli, Italy, 80131
    • S.C. Farmacia
  • Napoli, Italy, 80131
    • S.C. Medicina Nucleare e Terapia Metabolica
  • Napoli, Italy, 80131
    • SC Melanoma, Immunoterapia Oncologica e Terapie Innovative
  • Napoli, Italy, 80131
    • U.O. Radiodiagnostica 1
  • Naples
    • Napoli, Naples, Italy, 80131
      • Azienda Universitaria Policlinico Federico II
• United States
  • California
    • Los Angeles, California, United States, 90025
      • The Angeles Clinic and Research Institute, A Cedars-Sinai Affiliate
    • San Francisco, California, United States, 94143
      • UCSF Helen Diller Family Comprehensive Cancer Center
    • Santa Monica, California, United States, 90404
      • The Retina Partners
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital
    • Aurora, Colorado, United States, 80045
      • Rocky Mountain Lions Eye Institute (RMLEI)
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver CTO/CTRC - Outpatient.
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital - Anschutz Outpatient Pavilion
  • Oregon
    • Portland, Oregon, United States, 97239
      • OHSU Center for Health and Healing
    • Portland, Oregon, United States, 97239-3011
      • Oregon Health & Science University Center for Health & Healing 2
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

  1. 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.
  2. Phase 2 Arm A Cohort 2: Received no prior local therapy (e.g., brain surgery, craniotomy, SRS or SRT) for brain metastases.
  3. All patients (Safety Lead-In and Phase 2): May have received prior immunotherapy.
  4. 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:

  1. Radiation therapy to non-brain visceral metastasis within 2 weeks prior to start of study treatment;
  2. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standard Dose Arm; Patients in the standard-dose treatment arm will receive encorafenib and binimetinib in 28-day cycles.; 450 mg encorafenib orally once a day (QD); 45 mg binimetinib orally twice a day (BID) 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.	Drug: encorafenib; taken orally; Drug: binimetinib; taken orally
Experimental: High Dose Arm; Patients in the high-dose treatment arm will receive encorafenib and binimetinib in 28-day cycles.; 300 mg encorafenib orally twice a day (BID); 45 mg binimetinib orally twice a day (BID)	Drug: encorafenib; taken orally; Drug: binimetinib; taken orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose Limiting Toxicities (DLTs): Safety Lead-in (SLI) Phase	DLT: any adverse event (AE) or laboratory abnormality not explained by underlying disease/disease progression/intercurrent illness/concomitant therapies/resulting in inability to tolerate 75% of planned dose of binimetinib or encorafenib during Cycle 1. Left ventricular ejection fraction (LVEF) >10%, Grade (G)>=3 cardiac disorders; G3/4 hypertension vascular disorders; G3/4 rash, hand foot skin reaction, photosensitivity; G3/4 diarrhea, nausea/vomiting Total bilirubin (TBL) G>=3 (>3.0*upper limit of normal [ULN)]);AST/ALT>5-8*ULN>5 days,>8*ULN,>3*ULN concurrent TBL>2*ULN;G>=3 serum creatinine, CK elevation, ECG QTcF prolonged,G3 troponin, electrolyte>72 hours,G3/4 amylase/lipase.G4 ANC, platelet count>7 days;G3/4 platelet count, other AE except lymphopenia. G>=3 retinopathy, other disorder>21 days; G2 uveitis/eye pain/blurred vision/decreased visual acuity; G4 other disorder; Other hematologic/non hematologic G>=3 AE. This outcome measure was planned to be analyzed in SLI phase only.	Cycle 1 of SLI phase (up to 28 days)
Number of Participants With Treatment Emergent Adverse Events Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI _CTCAE) Version (v) 4.03: SLI Phase	AE: any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs: events between first dose of study drug up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state or start of subsequent anticancer drug therapy minus 1 day, whichever occurred first. Grades by NCI CTCAE v.4.03: Grade 1= asymptomatic or mild , clinical or diagnostic observations only, intervention not indicated; Grade 2= moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3= severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4= life-threatening consequence, urgent intervention indicated; Grade 5= death related to AE. Number of participants with AEs per maximum grades were reported.	Day 1 of dosing up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
Number of Participants With Hepatology Laboratory Test Abnormalities: SLI Phase	Hepatology laboratory abnormalities included following parameters: alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT or AST greater than or equal to (>=) 3*upper limit normal (ULN), >=5*ULN, >=10*ULN, >=20*ULN; total bilirubin (TBILI): >=2*ULN; ALT >=3*ULN and TBILI >=2*ULN; AST >=3*ULN and TBILI >=2*ULN; ALT or AST >=3*ULN and TBILI >=2*ULN; ALT or AST >=3*ULN and TBILI >=2*ULN and ALP >2*ULN; ALT or AST >=3*ULN and TBILI >=2*ULN and ALP <=2*ULN or missing. Only those laboratory test parameters in which at least 1 participant had data were reported.	Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase	Hematology and coagulation laboratory test included: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, international normalized ratio (INR) increased, leukocytosis, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased, and white blood cell decreased. Laboratory results were categorically summarized according to the NCI-CTCAE criteria v4.03. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Grade 0 was assigned for all non-missing values not graded as 1 or higher per CTCAE criteria. Number of participants with shift from baseline for hematology and coagulation laboratory test were assessed. Only those laboratory test parameters in which at least 1 participant had data were reported.	Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase	Biochemistry laboratory test included: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatine kinase (CK) increased, creatinine increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, lipase increased, and serum amylase increased. Laboratory results were categorically summarized according to the NCI-CTCAE criteria v4.03. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Grade 0 was assigned for all non-missing values not graded as 1 or higher per CTCAE criteria. Number of participants with shift from baseline for biochemistry laboratory test were assessed. Only those laboratory test parameters in which at least 1 participant had data were reported.	Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
Number of Participants With Notable Abnormal Vital Signs: SLI Phase	Vital signs included: systolic and diastolic blood pressure (BP),pulse rate,weight and temperature.Systolic and diastolic BP was measured in millimeters of mercury (mmHg) based on criteria:High Systolic BP:>=160 mmHg and increase >=20 mmHg from baseline;High Diastolic BP:>=100 mmHg and increase>=15 mmHg from baseline;Low Systolic BP:<=90 mmHg with decrease from baseline of >=20 mmHg;Low Diastolic BP:<=50 mmHg with decrease from baseline of >=15 mmHg;Pulse rate was measured in beats per minute (bpm) based on criteria:High pulse rate >=120 bpm with increase from baseline of >=15 bpm;Low pulse rate <=50 bpm with decrease from baseline of >=15 bpm;Weight was measured in in kilogram (kg) based on criteria:Increase from baseline of >=10%,:>=20% decrease from baseline;Temperature was measured in degree Celsius (C) based on criteria:High body temperature >=37.5 degree C,Low body temperature <=36 degree C.Only those vital signs parameters in which at least 1 participant had data were reported.	Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
Number of Participants With Notable Abnormal Electrocardiogram (ECG) Values: SLI Phase	In this outcome measure, number of participants with notable abnormal ECG values included: Fridericia's Correction Formula (QTcF) values in millisecond (msec) based on following criteria: 1) Increase from baseline >30 msec; 2) Increase from baseline >60 msec; 3) New >450 msec; 4) New >480 msec; and 5) New >500 msec; heart rate values in bpm based on following criteria: 1) Increase from baseline >25% and to a value >100; 2) Decrease from baseline >25% and to a value <50. Only those ECG parameters in which at least 1 participant had data were reported.	Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
Number of Participants With Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to AEs: SLI Phase	An AE is any untoward medical occurrence in clinical investigation participant administered a product or medical device; event need not necessarily to have a causal relationship with treatment or usage. In this outcome measure, number of participants with incidence of dose interruptions, dose modifications and discontinuations due to AEs were reported.	Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
Brain Metastasis Response Rate (BMRR) Based on Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (mRECIST v1.1): Phase 2	BMRR was reported in terms of percentage of participants who achieved a confirmed best overall response (BOR) of confirmed complete response (CR) or partial response (PR) in brain metastasis per mRECIST v1.1 from date of first dose until disease progression, death due to any cause, or start of subsequent anticancer therapy, whichever occurred first. BOR: best response recorded from date of first dose of study treatment until progression by investigator assessment at each time point. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.	From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in Phase 2 (approximately up to 8.3 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Extracranial Response Rate Based on RECIST v1.1: SLI Phase and Phase 2	Extracranial response rate was defined as the percentage of participants with a BOR of confirmed CR or confirmed PR in extracranial lesions by investigator assessment per RECIST v1.1. BOR: best response recorded from date of first dose of study treatment until progression by investigator assessment at each time point. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.	From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
Global Response Rate: SLI Phase and Phase 2	Global response rate was defined as the percentage of participants with a BOR of confirmed CR or confirmed PR by investigator assessment in brain metastasis and extracranial lesions per combined mRECIST v1.1 and RECIST v1.1, respectively. BOR: best response recorded from date of first dose of study treatment until progression by investigator assessment at each time point. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum of the diameters (e.g., percent change from baseline).	From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
Disease Control Rate (DCR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2	DCR was defined as the percentage of participants with a BOR of CR, PR or stable disease (SD) by Investigator assessment per mRECIST v1.1. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded since the treatment started.	From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
DCR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2	DCR was defined as the percentage of participants with a BOR of CR, PR or SD by Investigator assessment per RECIST v1.1. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum demonstrates an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.	From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
DCR for Global Response: SLI Phase and Phase 2	DCR was defined as the percentage of participants with a BOR of CR, PR or SD by Investigator assessment per RECIST v1.1. CR: disappearance of all target lesions. Any pathological lymph nodes must be <10 mm on the short axis. PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum of the diameters (e.g., percent change from baseline). SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to quality for PD. PD: at least a 20% increase in the sum of the diameters of target lesions, taking as a reference the smallest sum of diameters recorded since the treatment started (i.e., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of at least 5 mm.	From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
Duration of Response (DOR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2	DOR: time from date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. DOR (months) = (date of event or censoring - date of first CR or PR + 1)/30.4375. If a participant with a CR or PR did not have an event at time of analysis cutoff or with an event more than 16 weeks (for first 11 cycles after treatment start date) or 24 weeks (after Cycle 11) after last adequate tumor assessment, participant was censored on date of last adequate tumor assessment that documented no progression.	From date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
DOR for Global Response: SLI Phase and Phase 2	DOR: time from date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause. CR: disappearance of all target lesions. Any pathological lymph nodes must be <10 mm on the short axis. PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum of the diameters (e.g., percent change from baseline). DOR (months) = (date of event or censoring - date of first CR or PR + 1)/30.4375. If a participant with a CR or PR did not have an event at time of analysis cutoff or with an event more than 16 weeks (for first 11 cycles after treatment start date) or 24 weeks (after Cycle 11) after last adequate tumor assessment, participant was censored on date of last adequate tumor assessment that documented no progression.	From date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
DOR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2	DOR: time from date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. DOR (months) = (date of event or censoring - date of first CR or PR + 1)/30.4375. If a participant with a CR or PR did not have an event at time of analysis cutoff or with an event more than 16 weeks (for first 11 cycles after treatment start date) or 24 weeks (after Cycle 11) after last adequate tumor assessment, participant was censored on date of last adequate tumor assessment that documented no progression.	From date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2	PFS was defined as the time from date of the first dose of study treatment to the earliest documented disease progression (PD) by Investigator assessment, or death due to any cause, whichever occurs first. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase of at least 5 mm. If a participant did not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment.	From date of first dose of study treatment to the earliest documented disease progression by investigator assessment, or death due to any cause, whichever occurs first in SLI (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
PFS for Global Tumor Assessment: SLI Phase and Phase 2	PFS was defined as the time from date of the first dose of study treatment to the earliest documented disease progression (PD) by Investigator assessment, or death due to any cause, whichever occurs first. PD: at least a 20% increase in the sum of the diameters of target lesions, taking as a reference the smallest sum of diameters recorded since the treatment started (i.e., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of at least 5 mm. Global tumor assessment consists of brain metastasis and extracranial lesions. If a participant did not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment.	From date of first dose of study treatment to the earliest documented disease progression by investigator assessment, or death due to any cause, whichever occurs first in SLI (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
BMRR Based on mRECIST v1.1: SLI Phase	BMRR: percentage of participants who achieved a confirmed best overall response (BOR) of confirmed CR or PR in brain metastasis per mRECIST v1.1 from date of first dose until disease progression, death due to any cause, or start of subsequent anticancer therapy, whichever occurs first. BOR: best response recorded from date of first dose of study treatment until progression by investigator assessment at each time point. CR: Disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters (e.g., percent change from baseline).	From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months)
Overall Survival: SLI Phase and Phase 2	Overall survival (OS) was defined as the time from date of the first dose of study treatment to the date of death due to any cause. If a death was not observed by the date of the analysis cutoff, OS was censored at the date of last contact. OS (months) = (date of death or censoring - date of first dose +1)/30.4375	From date of first dose of study treatment to the earliest documented disease progression by investigator assessment, or death due to any cause, whichever occurs first in SLI (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
Number of Participants With Treatment Emergent AEs of Maximum Severity Grades Based on NCI CTCAE v4.03: Phase 2	AE was any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship.TEAEs were events between 1st dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state or start of subsequent anticancer drug therapy minus 1 day, whichever occurs first.Severity was graded by NCI CTCAE v.4.03.Grade 1:asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated;Grade 2:moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL;Grade 3:severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL;Grade 4:life-threatening consequence, urgent intervention indicated; Grade 5:death related to AE. Only those categories in which at least 1 participant had data were reported.	Day 1 of dosing up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months
Number of Participants With Hepatology Laboratory Test Abnormalities: Phase 2	Hepatology laboratory abnormalities included following parameters: ALT, AST, ALT or AST >=3*ULN, >=5*ULN, >=10*ULN, >=20*ULN; TBILI: >=2*ULN; ALT >=3*ULN and TBILI >=2*ULN; AST >=3*ULN and TBILI >=2*ULN; ALT or AST >=3*ULN and TBILI >=2*ULN; ALT or AST >=3*ULN and TBILI >=2*ULN and ALP >2*ULN; ALT or AST >=3*ULN and TBILI >=2*ULN and ALP <=2*ULN or missing. Only those laboratory test parameters in which at least 1 participant had data were reported.	Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months
Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2	Hematology and coagulation laboratory test included: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, INR increased, leukocytosis, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased, and white blood cell decreased. Laboratory results were categorically summarized according to the NCI-CTCAE criteria v4.03. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Grade 0 was assigned for all non-missing values not graded as 1 or higher per CTCAE criteria. Number of participants with shift from baseline for hematology and coagulation laboratory test were assessed. Only those laboratory test parameters in which at least 1 participant had data were reported.	Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months
Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2	Biochemistry laboratory test included: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, CK increased, creatinine increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, lipase increased, and serum amylase increased. Laboratory results were categorically summarized according to the NCI-CTCAE criteria v4.03. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Grade 0 was assigned for all non-missing values not graded as 1 or higher per CTCAE criteria. Number of participants with shift from baseline for biochemistry laboratory test were assessed. Only those laboratory test parameters in which at least 1 participant had data were reported.	Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months
Number of Participants With Clinically Significant Change in Notable Abnormal Vital Signs: Phase 2	In this outcome measure, number of participants with notable abnormal vital signs included: systolic and diastolic BP in mmHg based on following criteria: 1) High Systolic BP: >=160 mmHg and an increase >=20 mmHg from baseline; 2) High Diastolic BP: >=100 mmHg and an increase >=15 mmHg from baseline; 3) Low Systolic BP: <=90 mmHg with decrease from baseline of >=20 mmHg; 4) Low Diastolic BP: <=50 mmHg with decrease from baseline of >=15 mmHg; pulse rate in bpm based on following criteria: 1) High pulse rate >=120 bpm with increase from baseline of >=15 bpm; 2) Low pulse rate <=50 bpm with decrease from baseline of >=15 bpm; weight in kg based on following criteria: 1) Weight: Increase from baseline of >=10%, 2) Weight: >=20 % decrease from baseline; temperature in degree C based on following criteria: 1) High body temperature >=37.5 degree C, 2) Low body temperature <=36 degree C. Only those vital signs parameters in which at least 1 participant had data were reported.	Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months
Number of Participants With Notable Abnormal Electrocardiogram (ECG) Values: Phase 2	In this outcome measure, number of participants with notable abnormal ECG values included: QTcF values in msec based on following criteria: 1) increase from baseline >30 msec; 2) increase from baseline >60 msec; 3) new >450 msec; 4) new >480 msec; and 5) new >500 msec; heart rate values in bpm based on following criteria: 1) Increase from baseline >25% and to a value >100; 2) Decrease from baseline >25% and to a value <50. Only those vital ECG parameters in which at least 1 participant had data were reported.	Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months
Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase	In this outcome measure, plasma concentrations (in nanogram per milliliter [ng/mL]) of encorafenib and its metabolite LHY746 at Cycle 1 Day 1 (C1D1), Cycle 1 Day 15 (C1D15), Cycle 2 Day 1 (C2D1), and Cycle 3 Day 1 (C3D1) at different time points were reported.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose; Pre-dose on Cycle 2 Day 1, Cycle 3 Day 1
Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase	In this outcome measure, plasma concentrations of binimetinib and its metabolite AR00426032 at C1D1, C1D15, C2D1, and C3D1 at different time points were reported.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose; Pre-dose on Cycle 2 Day 1, Cycle 3 Day 1
Area Under the Plasma Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6) of Encorafenib and Its Metabolite LHY746: SLI Phase	In this outcome measure, area under the plasma concentration-time curve from zero to 6 hours (AUC 0-6) after administration of encorafenib and its metabolite LHY746 in nanogram*hour per milliliter (ng*hr/mL) at C1D1, and C1D15 were assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
AUC0-6 of Binimetinib and Its Metabolite AR00426032: SLI Phase	In this outcome measure, area under the plasma concentration-time curve from zero to 6 hours (AUC 0-6) after administration of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Area Under the Plasma Concentration-time Curve From Time Zero to Last Time Point (AUClast) of Encorafenib and Its Metabolite LHY746: SLI Phase	In this outcome measure, area under the plasma concentration-time curve from zero to the last measurable time point (AUClast) after administration of encorafenib and its metabolite LHY746 at C1D1, and C1D15 were assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
AUClast of Binimetinib and Its Metabolite AR00426032: SLI Phase	In this outcome measure, area under the plasma concentration-time curve from zero to the last measurable time point (AUClast) after administration of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Area Under the Plasma Concentration-time Curve From Time Zero to Tau (AUCtau) of Encorafenib and Its Metabolite LHY746: SLI Phase	In this outcome measure, area under the plasma concentration-time curve from time zero to the last measurable time point Tau (AUCtau) of encorafenib and its metabolite LHY746 over a dosing interval (6 hours as appropriate) of C1D15 were assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
AUCtau of Binimetinib and Its Metabolite AR00426032: SLI Phase	In this outcome measure, area under the plasma concentration-time curve from time zero to the last measurable time point Tau (AUCtau) of encorafenib and its metabolite LHY746 over a dosing interval (6 hours as appropriate) of C1D15 were assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Maximum Observed Plasma Concentration (Cmax) After Drug Administration of Encorafenib and Its Metabolite LHY746: SLI Phase	In this outcome measure, maximum observed plasma concentration (Cmax) after administration of encorafenib and its metabolite LHY746 at C1D1, and C1D15 were assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Cmax of Binimetinib and Its Metabolite AR00426032: SLI Phase	In this outcome measure, maximum observed plasma concentration (Cmax) after administration of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Minimum Observed Plasma Concentration (Cmin) at the End of a Dosing Interval at Steady State of Encorafenib and Its Metabolite LHY746: SLI Phase	In this outcome measure, minimum observed plasma concentration (Cmin) after administration of encorafenib and its metabolite LHY746 at C1D15 were assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Cmin of Binimetinib and Its Metabolite AR00426032: SLI Phase	In this outcome measure, minimum observed plasma concentration (Cmin) after administration of binimetinib and its metabolite AR00426032 at C1D15 were assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Ctrough of Encorafenib and Its Metabolite LHY746: SLI Phase	In this outcome measure, measured concentration at the end of a dosing interval (Ctrough) of encorafenib and its metabolite LHY746 at C1D15 were assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose; Pre-dose on Cycle 2 Day 1, Cycle 3 Day 1
Ctrough of Binimetinib and Its Metabolite AR00426032: SLI Phase	In this outcome measure, measured concentration at the end of a dosing interval (Ctrough) of binimetinib and its metabolite AR00426032 at C1D15 were assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose; Pre-dose on Cycle 2 Day 1, Cycle 3 Day 1
Time to Reach Maximum Concentration (Tmax) of Encorafenib and Its Metabolite LHY746: SLI Phase	In this outcome measure, time to reach maximum concentration (Tmax) of encorafenib and its metabolite LHY746 at C1D1, and C1D15 were assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Tmax of Binimetinib and Its Metabolite AR00426032: SLI Phase	In this outcome measure, time to reach maximum concentration (Tmax) of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hrs (+/- 20 minutes [min]) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs (+/- 20 min) post-dose
Time of Last PK Sample (Tlast) of Encorafenib and Its Metabolite LHY746: SLI Phase	In this outcome measure, time of last PK sample (Tlast) of encorafenib and its metabolite LHY746 at C1D1, and C1D15 were assessed. As outlined in the prespecified Statistical Analysis Plan for the study, since encorafenib was administered in continuous cycles, the pre-dose sample on Cycle 2 Day 1 was assumed to be at steady state and was interpolated as the concentration on 24 hours for encorafenib and LHY746 on Cycle 1 Day 15 during the analysis. In doing so, the reported Tlast values from the noncompartmental analysis (NCA) are 24 hours for encorafenib and LHY746.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6, 24 hrs post-dose
Tlast of Binimetinib and Its Metabolite AR00426032: SLI Phase	In this outcome measure, time of last PK sample (Tlast) of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed. As outlined in the prespecified Statistical Analysis Plan for the study, since binimetinib was administered in continuous cycles, the pre-dose sample on Cycle 2 Day 1 was assumed to be at steady state and was interpolated as the concentration for 12 hours for binimetinib and AR00426032 on Cycle 1 Day 15 for the noncompartmental analysis. In doing so, the reported Tlast values from the noncompartmental analysis (NCA) are 12 hours for binimetinib and AR00426032.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6, 12 hrs post-dose
Accumulation Ratio Between AUClast,ss and AUClast (RAUC) of Encorafenib and Its Metabolite LHY746: SLI Phase	In this outcome measure, accumulation ratio of encorafenib and its metabolite LHY746 calculated as: C1D15 AUC0-6 divided by C1D1 AUC0-6 was assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
RAUC of Binimetinib and Its Metabolite AR00426032: SLI Phase	In this outcome measure, accumulation ratio of binimetinib and its metabolite AR00426032 calculated as: C1D15 AUC0-6 divided by C1D1 AUC0-6 was assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Accumulation Ratio Between Cmax,ss and Cmax (RCmax) of Encorafenib and Its Metabolite LHY746: SLI Phase	In this outcome measure, accumulation ratio of encorafenib and its metabolite LHY746 calculated as: C1D15 Cmax divided by C1D1 Cmax was assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Rcmax of Binimetinib and Its Metabolite AR00426032: SLI Phase	In this outcome measure, accumulation ratio of binimetinib and its metabolite AR00426032 calculated as: C1D15 Cmax divided by C1D1 Cmax was assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) of LHY746: SLI Phase	In this outcome measure, ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, for LHY746/encorafenib at C1D1, and C1D15 was assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
MRAUClast of AR00426032: SLI Phase	In this outcome measure, ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, for AR00426032/binimetinib at C1D1, and C1D15 was assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) of LHY746: SLI Phase	In this outcome measure, ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, for LHY746/encorafenib at C1D1, and C1D15 was assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
MRCmax of AR00426032: SLI Phase	In this outcome measure, ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, for AR00426032/ binimetinib at C1D1, and C1D15 was assessed.	Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2019
• Primary Completion (Actual): January 27, 2022
• Study Completion (Actual): January 27, 2022

Study Registration Dates

• First Submitted: March 14, 2019
• First Submitted That Met QC Criteria: April 9, 2019
• First Posted (Actual): April 11, 2019

Study Record Updates

• Last Update Posted (Actual): May 31, 2023
• Last Update Submitted That Met QC Criteria: May 30, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: melanoma; brain metastasis; BRAFV600-mutant
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Neuroendocrine Tumors; Nevi and Melanomas; Neoplasm Metastasis; Brain Neoplasms; Melanoma
• Other Study ID Numbers: ARRAY-818-201; C4221006 (Other Identifier: Alias Study Number); 2018-004555-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No