Clinical trial NCT03911869: 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
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
Overall status: TERMINATED
Phase: PHASE2
Conditions: Brain Metastases
Keywords: BRAFV600-mutant
melanoma
brain metastasis
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2019-04-11
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


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:

  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.

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs): Safety Lead-in (SLI) Phase
timeFrame: Cycle 1 of SLI phase (up to 28 days)
measure: 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
timeFrame: Day 1 of dosing up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
measure: Number of Participants With Hepatology Laboratory Test Abnormalities: SLI Phase
timeFrame: Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
measure: Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase
timeFrame: Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
measure: Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase
timeFrame: Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
measure: Number of Participants With Notable Abnormal Vital Signs: SLI Phase
timeFrame: Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
measure: Number of Participants With Notable Abnormal Electrocardiogram (ECG) Values: SLI Phase
timeFrame: Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
measure: Number of Participants With Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to AEs: SLI Phase
timeFrame: Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
measure: Brain Metastasis Response Rate (BMRR) Based on Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (mRECIST v1.1): Phase 2
timeFrame: 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:
measure: Extracranial Response Rate Based on RECIST v1.1: SLI Phase and Phase 2
timeFrame: 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)
measure: Global Response Rate: SLI Phase and Phase 2
timeFrame: 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)
measure: Disease Control Rate (DCR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2
timeFrame: 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)
measure: DCR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2
timeFrame: 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)
measure: DCR for Global Response: SLI Phase and Phase 2
timeFrame: 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)
measure: Duration of Response (DOR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2
timeFrame: 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)
measure: DOR for Global Response: SLI Phase and Phase 2
timeFrame: 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)
measure: DOR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2
timeFrame: 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)
measure: Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2
timeFrame: 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)
measure: PFS for Global Tumor Assessment: SLI Phase and Phase 2
timeFrame: 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)
measure: BMRR Based on mRECIST v1.1: SLI Phase
timeFrame: 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)
measure: Overall Survival: SLI Phase and Phase 2
timeFrame: 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)
measure: Number of Participants With Treatment Emergent AEs of Maximum Severity Grades Based on NCI CTCAE v4.03: Phase 2
timeFrame: Day 1 of dosing up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months
measure: Number of Participants With Hepatology Laboratory Test Abnormalities: Phase 2
timeFrame: Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months
measure: Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2
timeFrame: Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months
measure: Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2
timeFrame: Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months
measure: Number of Participants With Clinically Significant Change in Notable Abnormal Vital Signs: Phase 2
timeFrame: Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months
measure: Number of Participants With Notable Abnormal Electrocardiogram (ECG) Values: Phase 2
timeFrame: Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months
measure: Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase
timeFrame: 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
measure: Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase
timeFrame: 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
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6) of Encorafenib and Its Metabolite LHY746: SLI Phase
timeFrame: 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
measure: AUC0-6 of Binimetinib and Its Metabolite AR00426032: SLI Phase
timeFrame: 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
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Last Time Point (AUClast) of Encorafenib and Its Metabolite LHY746: SLI Phase
timeFrame: 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
measure: AUClast of Binimetinib and Its Metabolite AR00426032: SLI Phase
timeFrame: 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
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Tau (AUCtau) of Encorafenib and Its Metabolite LHY746: SLI Phase
timeFrame: 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
measure: AUCtau of Binimetinib and Its Metabolite AR00426032: SLI Phase
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) After Drug Administration of Encorafenib and Its Metabolite LHY746: SLI Phase
timeFrame: 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
measure: Cmax of Binimetinib and Its Metabolite AR00426032: SLI Phase
timeFrame: 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
measure: Minimum Observed Plasma Concentration (Cmin) at the End of a Dosing Interval at Steady State of Encorafenib and Its Metabolite LHY746: SLI Phase
timeFrame: 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
measure: Cmin of Binimetinib and Its Metabolite AR00426032: SLI Phase
timeFrame: 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
measure: Ctrough of Encorafenib and Its Metabolite LHY746: SLI Phase
timeFrame: 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
measure: Ctrough of Binimetinib and Its Metabolite AR00426032: SLI Phase
timeFrame: 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
measure: Time to Reach Maximum Concentration (Tmax) of Encorafenib and Its Metabolite LHY746: SLI Phase
timeFrame: 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
measure: Tmax of Binimetinib and Its Metabolite AR00426032: SLI Phase
timeFrame: 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
measure: Time of Last PK Sample (Tlast) of Encorafenib and Its Metabolite LHY746: SLI Phase
timeFrame: 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
measure: Tlast of Binimetinib and Its Metabolite AR00426032: SLI Phase
timeFrame: 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
measure: Accumulation Ratio Between AUClast,ss and AUClast (RAUC) of Encorafenib and Its Metabolite LHY746: SLI Phase
timeFrame: 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
measure: RAUC of Binimetinib and Its Metabolite AR00426032: SLI Phase
timeFrame: 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
measure: Accumulation Ratio Between Cmax,ss and Cmax (RCmax) of Encorafenib and Its Metabolite LHY746: SLI Phase
timeFrame: 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
measure: Rcmax of Binimetinib and Its Metabolite AR00426032: SLI Phase
timeFrame: 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
measure: Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) of LHY746: SLI Phase
timeFrame: 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
measure: MRAUClast of AR00426032: SLI Phase
timeFrame: 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
measure: Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) of LHY746: SLI Phase
timeFrame: 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
measure: MRCmax of AR00426032: SLI Phase
timeFrame: 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
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: The Angeles Clinic And Research Institute, A Cedars-Sinai Affiliate
state: California
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
city: Santa Monica
country: United States
facility: The Retina Partners
state: California
city: Aurora
country: United States
facility: Rocky Mountain Lions Eye Institute (RMLEI)
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Denver CTO/CTRC - Outpatient.
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Hospital - Anschutz Outpatient Pavilion
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Portland
country: United States
facility: Oregon Health & Science University Center for Health & Healing 2
state: Oregon
city: Portland
country: United States
facility: OHSU Center for Health and Healing
state: Oregon
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Buenos Aires
country: Argentina
facility: Instituto Médico Especializado Alexander Fleming
state: Ciudad Autónoma DE Buenosaires
city: Rosario
country: Argentina
facility: Instituto de Oncologia de Rosario
state: Santa FE
city: Caba
country: Argentina
facility: Fundacion CIDEA
city: Crows Nest
country: Australia
facility: Crows Nest Eye Surgery
state: New South Wales
city: North Sydney
country: Australia
facility: Melanoma Institute Australia
state: New South Wales
city: st Leonards
country: Australia
facility: Royal north shore center hospital dermatology clinics
state: New South Wales
city: Wollstonecraft
country: Australia
facility: Mater Imaging
state: New South Wales
city: Edegem
country: Belgium
facility: UZ Antwerpen
state: Antwerpen
city: Napoli
country: Italy
facility: Azienda Universitaria Policlinico Federico II
state: Naples
city: Napoli
country: Italy
facility: S.C. Cardiologia
city: Napoli
country: Italy
facility: S.C. Farmacia
city: Napoli
country: Italy
facility: S.C. Medicina Nucleare e Terapia Metabolica
city: Napoli
country: Italy
facility: SC Melanoma, Immunoterapia Oncologica e Terapie Innovative
city: Napoli
country: Italy
facility: U.O. Radiodiagnostica 1
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: