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

Phase 2TerminatedNCT03911869

Pfizer13 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Brain Metastases

Interventions

encorafenib

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (25)

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

Los Angeles, California, United States

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, California, United States

The Retina Partners

Santa Monica, California, United States

Rocky Mountain Lions Eye Institute (RMLEI)

Aurora, Colorado, United States

University of Colorado Denver CTO/CTRC - Outpatient.

Aurora, Colorado, United States

University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)

Aurora, Colorado, United States

University of Colorado Hospital - Anschutz Outpatient Pavilion

Aurora, Colorado, United States

University of Colorado Hospital

Aurora, Colorado, United States

Oregon Health & Science University Center for Health & Healing 2

Portland, Oregon, United States

OHSU Center for Health and Healing

Portland, Oregon, United States

...and 15 more locations

Outcomes

Primary Outcomes

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.

Time frame: 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.

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

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.