Safety and Efficacy in Participants With Metastatic BRAF-mutant Melanoma Treated With Encorafenib With and Without Binimetinib in Combination With Nivolumab and Low-dose Ipilimuma

NCT04655157 | Terminated Phase 1 Results DMC FDA Drug

• 2 other identifiers: HCC 20-190CA209-7Y4
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

Patients with unresectable or metastatic BRAF-mutant melanoma high-risk patients will be given 450 mg orally (PO) daily (QD) plus binimetinib 45 mg PO twice daily (BID) together with nivolumab administered intravenously (IV) at 3mg/kg and ipilimumab administered IV at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab administered IV at 480mg every 4 weeks until progression or discontinuation due to toxicity. Concurrently, a triple therapy arm will be explored with encorafenib 300 mg PO QD together with ipilimumab administered IV at 1mg/kg and nivolumab 3mg/kg IV every 3 weeks for 4 doses, followed by nivolumab administered at 480mg every 4 weeks until progression or discontinuation due to toxicity. Tolerability of the two arms will be compared, and a recommended phase 2 dose (RP2D) will be determined. After determination of treatment schedule, expansion cohorts will further explore the preliminary efficacy and further describe the toxicity profile of the triplet or quadruplet regimen in high-risk cohorts including symptomatic brain metastases or liver metastases with elevated lactate dehydrogenase (LDH) or bulky systemic disease burden.

Conditions

Melanoma

Keywords

BRAFV600E/K mutation; metastatic melanoma

Outcome Measures

Primary Outcomes (2)

• Recommended Phase II Dose (RP2D) of Encorafenib + Nivolumab + Ipilimumab

  Determination of recommended phase II dose (RP2D) of triple therapy in patients treated with 300mg encorafenib, 3mg/kg nivolumab and 1mg/kg ipilimumab via the frequency of DLTs that are classified as either possibly, probably, or definitely related to study treatment according to NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0). Number of distinct patients experiencing Adverse events and DLTs. This will be done with continuous Bayesian toxicity monitoring.

  Up to 6 weeks (DLT evaluation period)

• Recommended Phase II Dose (RP2D) of Encorafenib + Binimetinib + Nivolumab + Ipilimumab

  Determination of recommended phase II dose (RP2D) of quadruple therapy in patients treated with 450mg encorafenib, 45mg binimetinib, 3mg/kg nivolumab and 1mg/kg ipilimumab via the frequency of DLTs that are classified as either possibly, probably, or definitely related to study treatment according to NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0). Number of distinct patients experiencing Adverse events and DLTs. This will be done with continuous Bayesian toxicity monitoring.

  Up to 6 weeks (DLT evaluation period)

Secondary Outcomes (4)

• Response Rate Per RECIST v1.1 Criteria

  Up to 15 months

• Central Nervous System (CNS) Clinical Benefit Rate (CBR)

  Up to 15 months

• Adverse Events at Least Probably Related to Treatment

  Up to 6 months (per patient)

• Progression-free Survival (PFS)

  Up to 15 months

Study Arms (2)

Phase 1 (cohort 1): 300mg encorafenib + 3mg/kg nivolumab + 1 mg/kg ipilimumab

EXPERIMENTAL

Patients will be treated with 300mg encorafenib and 3mg/kg nivolumab and 1 mg/kg ipilimumab (triple therapy).

Drug: encorafenib; Drug: nivolumab; Drug: ipilimumab

Phase 1 (cohort 2): 450mg encorafenib + 45mg binimetinib + 3mg/kg nivolumab + 1mg/kg ipilimumab

EXPERIMENTAL

Patients will be treated with 450mg encorafenib, 45mg binimetinib, 3mg/kg nivolumab and 1mg/kg ipilimumab (quadruple therapy).

Drug: encorafenib; Drug: nivolumab; Drug: ipilimumab; Drug: binimetinib

Interventions

encorafenib DRUG

A small molecule BRAF inhibitor that targets key enzymes in the MAPK signaling pathway.

Also known as: BRAFTOVI®

Phase 1 (cohort 1): 300mg encorafenib + 3mg/kg nivolumab + 1 mg/kg ipilimumab; Phase 1 (cohort 2): 450mg encorafenib + 45mg binimetinib + 3mg/kg nivolumab + 1mg/kg ipilimumab

nivolumab DRUG

A programmed death receptor-1 (PD-1) blocking monoclonal antibody that works by helping the immune system to slow or stop the growth of cancer cells.

Also known as: OPDIVO®

Phase 1 (cohort 1): 300mg encorafenib + 3mg/kg nivolumab + 1 mg/kg ipilimumab; Phase 1 (cohort 2): 450mg encorafenib + 45mg binimetinib + 3mg/kg nivolumab + 1mg/kg ipilimumab

ipilimumab DRUG

A monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

Also known as: Yervoy®

Phase 1 (cohort 1): 300mg encorafenib + 3mg/kg nivolumab + 1 mg/kg ipilimumab; Phase 1 (cohort 2): 450mg encorafenib + 45mg binimetinib + 3mg/kg nivolumab + 1mg/kg ipilimumab

binimetinib DRUG

A small molecule, selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway that may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Also known as: Mektovi, ARRY-162

Phase 1 (cohort 2): 450mg encorafenib + 45mg binimetinib + 3mg/kg nivolumab + 1mg/kg ipilimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed Written Informed Consent
• Participants must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal subject care.
• Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.
• Age ≥18 years
• Histologically confirmed diagnosis of unresectable or metastatic melanoma
• Presence of BRAFV600E/K mutation in tumor tissue as determined in a CLIA certified laboratory
• Patients are required to submit archival biopsy material, if available, and submit research blood samples prior to first dose. Ten patients in each Phase Ib cohort will undergo fresh biopsy. These will be the first 10 unless medical or societal factors (e.g. COVID19) limit the pursuit of research biopsies.
• Patients must be greater than 6 months from completion of adjuvant therapy (if any given) and/or treatment naïve in the metastatic setting or have recently started targeted therapy within the last 6 weeks.
• Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration.
• An ECOG Performance Status of 0 or 1. If enrolling in Group 1 of Phase II, can have Performance Status from 0-2.
• Measurable disease by CT or MRI per RANO-BM (brain metastases) OR RECIST v1.1 criteria
• Must have high risk features described as described in Phase II expansion cohort - EITHER brain metastases as described in Phase II Group 1 OR Elevated LDH/Bulky Visceral Disease as described in Phase II Group 2.
• Adequate bone marrow, organ function, and laboratory parameters:
• ANC \> 1.5 x 109 ¬ /L;
• Hemoglobin \> 8 g/dL with or without transfusions;

You may not qualify if:

• Known hypersensitivity or contraindication to any component of study treatment or their excipients.
• Previous Grade 3-4 AEs, or discontinuation of PD-1 or CTLA-4 inhibitor therapy, or BRAF/MEK inhibitor therapy
• Inability to swallow and retain study treatment
• Impairment of gastrointestinal function or disease which may significantly alter the absorption of study treatment (e.g., active ulcerative disease; uncontrolled nausea, vomiting or diarrhea; malabsorption syndrome; small bowel resection).
• Participants with a non-melanoma related condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Participants with active, known or suspected autoimmune disease including those who have required systemic anti-rheumatic therapies in the preceding 2 years. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Impaired cardiovascular function or clinically significant cardiovascular disease including, but not limited to, the following:
• History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) \< 6 months prior to Screening
• Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2)
• A known LVEF \< 50% as determined by MUGA or ECHO
• Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy
• History or presence of clinically significant cardiac arrhythmias (including resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia)
• Baseline QTcF interval ≥ 480 ms.
• Second malignancy that requires active treatment or would interfere with treatment efficacy evaluation. Participants with a second malignancy treated with curative intent are eligible.
• On-going or use of systemic antibiotics during the preceding 2 weeks prior to enrollment

Sponsors & Collaborators

• Jason J. Luke, MD: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

MeSH Terms

Conditions

Melanoma

Interventions

encorafenib; Nivolumab; Ipilimumab; binimetinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Barbara M. Stadterman, MPH, MCCR
• Organization: UPMC Hillman Cancer Center

stadtermanbm@upmc.edu

412-647-5554

Study Officials

• Jason J Luke, MD

  UPMC Hillman Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: December 3, 2020
• First Posted: December 7, 2020
• Study Start: May 28, 2021
• Primary Completion: August 3, 2022
• Study Completion: September 20, 2022
• Last Updated: May 23, 2024
• Results First Posted: May 23, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)