NCT03911869|TerminatedPhase 2ResultsFDA Drug

Study 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.

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

Pfizer ClinicalTrials.gov

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3 other identifiers

ARRAY-818-201C42210062018-004555-21

Study Type

interventional

Target

Locations

5 countries

Sites

Timeline

RegisteredApr 2019

StartedApr 2019

CompletionJan 2022

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.

Trial Health

Monitor

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment

participants targeted

Target at below P25 for phase_2

Timeline

Completed

Started Apr 2019

Geographic Reach

5 countries

25 active sites

Status

terminated

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

2.7 years study duration

First Submitted

Initial submission to the registry

March 14, 2019

Completed

28 days until next milestone

First Posted

Study publicly available on registry

April 11, 2019

Completed

19 days until next milestone

Study Start

First participant enrolled

April 30, 2019

Completed

2.7 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

January 27, 2022

Completed

Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

January 27, 2022

Completed

1.3 years until next milestone

Results Posted

Study results publicly available

May 31, 2023

Completed

Last Updated

May 31, 2023

Status Verified

May 1, 2023

Enrollment Period

2.7 years

First QC Date

March 14, 2019

Results QC Date

January 5, 2023

Last Update Submit

May 30, 2023

Conditions

Brain Metastases

Keywords

BRAFV600-mutantmelanomabrain metastasis

Outcome Measures

Primary Outcomes (9)

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 Outcomes (44)

Extracranial Response Rate Based on RECIST v1.1: SLI Phase and Phase 2
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
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
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
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
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)
+39 more secondary outcomes

Study Arms (2)

Standard Dose Arm

EXPERIMENTAL

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: encorafenibDrug: binimetinib

High Dose Arm

EXPERIMENTAL

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: encorafenibDrug: binimetinib

Interventions

encorafenibDRUG

taken orally

High Dose ArmStandard Dose Arm

binimetinibDRUG

taken orally

High Dose ArmStandard Dose Arm

Eligibility Criteria

Age18 Years+

Sexall

Healthy VolunteersNo

Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

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.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Pfizerlead

Study Sites (25)

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

Los Angeles, California, 90025, United States

Location

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, California, 94143, United States

Location

The Retina Partners

Santa Monica, California, 90404, United States

Location

Rocky Mountain Lions Eye Institute (RMLEI)