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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)

Primary Purpose

Brain Metastases

Status

Terminated

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

encorafenib

binimetinib

About this trial

This is an interventional treatment trial for Brain Metastases focused on measuring BRAFV600-mutant, melanoma, brain metastasis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

The Angeles Clinic And Research Institute, A Cedars-Sinai Affiliate
UCSF Helen Diller Family Comprehensive Cancer Center
The Retina Partners
Rocky Mountain Lions Eye Institute (RMLEI)
University of Colorado Denver CTO/CTRC - Outpatient.
University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)
University of Colorado Hospital - Anschutz Outpatient Pavilion
University of Colorado Hospital
Oregon Health & Science University Center for Health & Healing 2
OHSU Center for Health and Healing
MD Anderson Cancer Center
Instituto Médico Especializado Alexander Fleming
Instituto de Oncologia de Rosario
Fundacion CIDEA
Crows Nest Eye Surgery
Melanoma Institute Australia
Royal north shore center hospital dermatology clinics
Mater Imaging
UZ Antwerpen
Azienda Universitaria Policlinico Federico II
S.C. Cardiologia
S.C. Farmacia
S.C. Medicina Nucleare e Terapia Metabolica
SC Melanoma, Immunoterapia Oncologica e Terapie Innovative
U.O. Radiodiagnostica 1

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Standard Dose Arm

High Dose Arm

Arm Description

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.

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)

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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.

Secondary Outcome Measures

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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).

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

AUCtau of Binimetinib and Its Metabolite AR00426032: SLI Phase

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT03911869

First Posted

March 14, 2019

Last Updated

May 30, 2023

Sponsor

Pfizer

1. Study Identification

Unique Protocol Identification Number

NCT03911869

Brief Title

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

Acronym

POLARIS

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Terminated

Why Stopped

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.

Study Start Date

April 30, 2019 (Actual)

Primary Completion Date

January 27, 2022 (Actual)

Study Completion Date

January 27, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Pfizer

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Brain Metastases

Keywords

BRAFV600-mutant, melanoma, brain metastasis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

13 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Standard Dose Arm

Arm Type

Experimental

Arm Description

Arm Title

High Dose Arm

Arm Type

Experimental

Arm Description

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)

Intervention Type

Drug

Intervention Name(s)

encorafenib

Intervention Description

taken orally

Intervention Type

Drug

Intervention Name(s)

binimetinib

Intervention Description

taken orally

Primary Outcome Measure Information:

Title

Number of Participants With Dose Limiting Toxicities (DLTs): Safety Lead-in (SLI) Phase

Description

Time Frame

Cycle 1 of SLI phase (up to 28 days)

Title

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

Description

Time Frame

Day 1 of dosing up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months

Title

Number of Participants With Hepatology Laboratory Test Abnormalities: SLI Phase

Description

Time Frame

Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months

Title

Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase

Description

Time Frame

Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months

Title

Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase

Description

Time Frame

Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months

Title

Number of Participants With Notable Abnormal Vital Signs: SLI Phase

Description

Time Frame

Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months

Title

Number of Participants With Notable Abnormal Electrocardiogram (ECG) Values: SLI Phase

Description

Time Frame

Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months

Title

Number of Participants With Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to AEs: SLI Phase

Description

Time Frame

Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months

Title

Brain Metastasis Response Rate (BMRR) Based on Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (mRECIST v1.1): Phase 2

Description

Time Frame

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 Measure Information:

Title

Extracranial Response Rate Based on RECIST v1.1: SLI Phase and Phase 2

Description

Time Frame

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)

Title

Global Response Rate: SLI Phase and Phase 2

Description

Time Frame

Title

Disease Control Rate (DCR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2

Description

Time Frame

Title

DCR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2

Description

Time Frame

Title

DCR for Global Response: SLI Phase and Phase 2

Description

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.

Time Frame

Title

Duration of Response (DOR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2

Description

Time Frame

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)

Title

DOR for Global Response: SLI Phase and Phase 2

Description

Time Frame

Title

DOR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2

Description

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.

Time Frame

Title

Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2

Description

Time Frame

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)

Title

PFS for Global Tumor Assessment: SLI Phase and Phase 2

Description

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.

Time Frame

Title

BMRR Based on mRECIST v1.1: SLI Phase

Description

Time Frame

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)

Title

Overall Survival: SLI Phase and Phase 2

Description

Time Frame

Title

Number of Participants With Treatment Emergent AEs of Maximum Severity Grades Based on NCI CTCAE v4.03: Phase 2

Description

Time Frame

Day 1 of dosing up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months

Title

Number of Participants With Hepatology Laboratory Test Abnormalities: Phase 2

Description

Time Frame

Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months

Title

Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2

Description

Time Frame

Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months

Title

Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2

Description

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.

Time Frame

Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months

Title

Number of Participants With Clinically Significant Change in Notable Abnormal Vital Signs: Phase 2

Description

Time Frame

Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months

Title

Number of Participants With Notable Abnormal Electrocardiogram (ECG) Values: Phase 2

Description

Time Frame

Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months

Title

Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase

Description

Time Frame

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

Title

Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase

Description

In this outcome measure, plasma concentrations of binimetinib and its metabolite AR00426032 at C1D1, C1D15, C2D1, and C3D1 at different time points were reported.

Time Frame

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

Title

Area Under the Plasma Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6) of Encorafenib and Its Metabolite LHY746: SLI Phase

Description

Time Frame

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

Title

AUC0-6 of Binimetinib and Its Metabolite AR00426032: SLI Phase

Description

Time Frame

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

Title

Area Under the Plasma Concentration-time Curve From Time Zero to Last Time Point (AUClast) of Encorafenib and Its Metabolite LHY746: SLI Phase

Description

Time Frame

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

Title

AUClast of Binimetinib and Its Metabolite AR00426032: SLI Phase

Description

Time Frame

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

Title

Area Under the Plasma Concentration-time Curve From Time Zero to Tau (AUCtau) of Encorafenib and Its Metabolite LHY746: SLI Phase

Description

Time Frame

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

Title

AUCtau of Binimetinib and Its Metabolite AR00426032: SLI Phase

Description

Time Frame

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

Title

Maximum Observed Plasma Concentration (Cmax) After Drug Administration of Encorafenib and Its Metabolite LHY746: SLI Phase

Description

In this outcome measure, maximum observed plasma concentration (Cmax) after administration of encorafenib and its metabolite LHY746 at C1D1, and C1D15 were assessed.

Time Frame

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

Title

Cmax of Binimetinib and Its Metabolite AR00426032: SLI Phase

Description

In this outcome measure, maximum observed plasma concentration (Cmax) after administration of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed.

Time Frame

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

Title

Minimum Observed Plasma Concentration (Cmin) at the End of a Dosing Interval at Steady State of Encorafenib and Its Metabolite LHY746: SLI Phase

Description

In this outcome measure, minimum observed plasma concentration (Cmin) after administration of encorafenib and its metabolite LHY746 at C1D15 were assessed.

Time Frame

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

Title

Cmin of Binimetinib and Its Metabolite AR00426032: SLI Phase

Description

In this outcome measure, minimum observed plasma concentration (Cmin) after administration of binimetinib and its metabolite AR00426032 at C1D15 were assessed.

Time Frame

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

Title

Ctrough of Encorafenib and Its Metabolite LHY746: SLI Phase

Description

In this outcome measure, measured concentration at the end of a dosing interval (Ctrough) of encorafenib and its metabolite LHY746 at C1D15 were assessed.

Time Frame

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

Title

Ctrough of Binimetinib and Its Metabolite AR00426032: SLI Phase

Description

In this outcome measure, measured concentration at the end of a dosing interval (Ctrough) of binimetinib and its metabolite AR00426032 at C1D15 were assessed.

Time Frame

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

Title

Time to Reach Maximum Concentration (Tmax) of Encorafenib and Its Metabolite LHY746: SLI Phase

Description

In this outcome measure, time to reach maximum concentration (Tmax) of encorafenib and its metabolite LHY746 at C1D1, and C1D15 were assessed.

Time Frame

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

Title

Tmax of Binimetinib and Its Metabolite AR00426032: SLI Phase

Description

In this outcome measure, time to reach maximum concentration (Tmax) of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed.

Time Frame

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

Title

Time of Last PK Sample (Tlast) of Encorafenib and Its Metabolite LHY746: SLI Phase

Description

Time Frame

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

Title

Tlast of Binimetinib and Its Metabolite AR00426032: SLI Phase

Description

Time Frame

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

Title

Accumulation Ratio Between AUClast,ss and AUClast (RAUC) of Encorafenib and Its Metabolite LHY746: SLI Phase

Description

In this outcome measure, accumulation ratio of encorafenib and its metabolite LHY746 calculated as: C1D15 AUC0-6 divided by C1D1 AUC0-6 was assessed.

Time Frame

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

Title

RAUC of Binimetinib and Its Metabolite AR00426032: SLI Phase

Description

In this outcome measure, accumulation ratio of binimetinib and its metabolite AR00426032 calculated as: C1D15 AUC0-6 divided by C1D1 AUC0-6 was assessed.

Time Frame

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

Title

Accumulation Ratio Between Cmax,ss and Cmax (RCmax) of Encorafenib and Its Metabolite LHY746: SLI Phase

Description

In this outcome measure, accumulation ratio of encorafenib and its metabolite LHY746 calculated as: C1D15 Cmax divided by C1D1 Cmax was assessed.

Time Frame

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

Title

Rcmax of Binimetinib and Its Metabolite AR00426032: SLI Phase

Description

In this outcome measure, accumulation ratio of binimetinib and its metabolite AR00426032 calculated as: C1D15 Cmax divided by C1D1 Cmax was assessed.

Time Frame

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

Title

Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) of LHY746: SLI Phase

Description

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.

Time Frame

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

Title

MRAUClast of AR00426032: SLI Phase

Description

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.

Time Frame

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

Title

Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) of LHY746: SLI Phase

Description

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.

Time Frame

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

Title

MRCmax of AR00426032: SLI Phase

Description

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.

Time Frame

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Pfizer CT.gov Call Center

Organizational Affiliation

Pfizer

Official's Role

Study Director

Facility Information:

Facility Name

The Angeles Clinic And Research Institute, A Cedars-Sinai Affiliate

City

Los Angeles

State/Province

California

ZIP/Postal Code

90025

Country

United States

Facility Name

UCSF Helen Diller Family Comprehensive Cancer Center

City

San Francisco

State/Province

California

ZIP/Postal Code

94143

Country

United States

Facility Name

The Retina Partners

City

Santa Monica

State/Province

California

ZIP/Postal Code

90404

Country

United States

Facility Name

Rocky Mountain Lions Eye Institute (RMLEI)

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

Facility Name

University of Colorado Denver CTO/CTRC - Outpatient.

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

Facility Name

University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

Facility Name

University of Colorado Hospital - Anschutz Outpatient Pavilion

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

Facility Name

University of Colorado Hospital

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

Facility Name

Oregon Health & Science University Center for Health & Healing 2

City

Portland

State/Province

Oregon

ZIP/Postal Code

97239-3011

Country

United States

Facility Name

OHSU Center for Health and Healing

City

Portland

State/Province

Oregon

ZIP/Postal Code

97239

Country

United States

Facility Name

MD Anderson Cancer Center

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

Instituto Médico Especializado Alexander Fleming

City

Buenos Aires

State/Province

Ciudad Autónoma DE Buenosaires

ZIP/Postal Code

CP1426ANZ

Country

Argentina

Facility Name

Instituto de Oncologia de Rosario

City

Rosario

State/Province

Santa FE

ZIP/Postal Code

S2000KZE

Country

Argentina

Facility Name

Fundacion CIDEA

City

Caba

ZIP/Postal Code

C1121ABE

Country

Argentina

Facility Name

Crows Nest Eye Surgery

City

Crows Nest

State/Province

New South Wales

ZIP/Postal Code

2065

Country

Australia

Facility Name

Melanoma Institute Australia

City

North Sydney

State/Province

New South Wales

ZIP/Postal Code

2060

Country

Australia

Facility Name

Royal north shore center hospital dermatology clinics

City

st Leonards

State/Province

New South Wales

ZIP/Postal Code

2065

Country

Australia

Facility Name

Mater Imaging

City

Wollstonecraft

State/Province

New South Wales

ZIP/Postal Code

2065

Country

Australia

Facility Name

UZ Antwerpen

City

Edegem

State/Province

Antwerpen

ZIP/Postal Code

2650

Country

Belgium

Facility Name

Azienda Universitaria Policlinico Federico II

City

Napoli

State/Province

Naples

ZIP/Postal Code

80131

Country

Italy

Facility Name

S.C. Cardiologia

City

Napoli

ZIP/Postal Code

80131

Country

Italy

Facility Name

S.C. Farmacia

City

Napoli

ZIP/Postal Code

80131

Country

Italy

Facility Name

S.C. Medicina Nucleare e Terapia Metabolica

City

Napoli

ZIP/Postal Code

80131

Country

Italy

Facility Name

SC Melanoma, Immunoterapia Oncologica e Terapie Innovative

City

Napoli

ZIP/Postal Code

80131

Country

Italy

Facility Name

U.O. Radiodiagnostica 1

City

Napoli

ZIP/Postal Code

80131

Country

Italy

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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.

IPD Sharing URL

https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

Links:

URL

https://pmiform.com/clinical-trial-info-request?StudyID=ARRAY-818-201

Description

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

Learn more about this trial

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

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