A randomized phase 2 trial of encorafenib + binimetinib + nivolumab vs ipilimumab + nivolumab in BRAFV600-mutant melanoma brain metastases

For a comprehensive list, see section 5.0 of the protocol.

Disease Related Criteria
Participants must have:
-histologically and pathologically confirmed melanoma that has metastasized to the brain.
-BRAF-V600 mutant melanoma documented by a CLIA-certified laboratory
-MRI of the brain within 28 days prior to registration and must have central nervous system metastases with at least one measurable brain metastasis ≥ 0.5cm in size that has not been irradiated, or progressed (in the opinion of the treating physician) after prior radiation therapy (per modified RECIST 1.1. see Section 10.4)
-measurable or non-measurable extracranial disease (see Section 10.1)
-may have leptomeningeal disease.
-a. Any primary (cutaneous, acral/mucosal,etc) or unknown origin are permitted, except that participants with uveal primary are not eligible.

Prior/Concurrent Therapy Criteria
Participants must not:
-have received prior systemic therapy for metastatic disease. Prior systemic therapy received only in the neoadjuvant and/or adjuvant setting (e.g., BRAF/MEK inhibitor therapy, anti-PD-1 therapy or anti-CTLA4 therapy, alfa-interferon, etc.) is permitted. If patients received prior neoadjuvant/adjuvant therapy, they must have had eventual disease relapse prior to randomization.
-have had prior radiation therapy within 7 days prior to randomization.
-be planning to require any additional form of systemic anti-tumor therapy for melanoma while on protocol treatment
-be planning to use hormonal contraceptives.
-Participants may be receiving corticosteroids for brain metastases at a dose of up to 8 mg of dexamethasone per day. The dose must not have exceeded 8 mg per day for at least 7 days prior to randomization.

Clinical/Laboratory Criteria
Participants must:
-be ≥ 18 years of age
-must have Zubrod Performance Status ≤ 2
-complete history and physical examination within 28 days prior to randomization
-be able to swallow and retain pills
-have adequate organ and marrow function as defined in section 5.0 of the protocol within 28 days prior to randomization
-class 2B or better using the New York Heart Association Functional Classification
-using the New York Heart Association Functional Classification
-not have active autoimmune disease that has required treatment in the past 6 months with use of biologic disease modifying agents
-not have had Grade 3 or 4 immune-related adverse events on ipilimumab or nivolumab that required more than 12 weeks of immune suppression with corticosteroids
-not have had adverse events related to encorafenib and/or binimetinib specifically, that required discontinuation of one or both drugs
-not be pregnant or nursing.
-Participants with a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
-Participants with known human immunodeficiency virus (HIV)-infection are eligible providing they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 90 days prior to randomization.
-Participants with a known history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with HCV infection who are currently on treatment must have an undetectable HCV viral load prior to randomization.

Specimen Submission Criteria
-Participants must agree to participate in image banking as outlined in Section 15.1, Images must be submitted submitted via the Triad System as outlined in Section 15.1b.
-Participants must be offered the opportunity to participate in specimen and blood collections as outlined as outlined in Section 15.2.

Regulatory Criteria
-Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines.
-As a part of the OPEN registration process (see Section 13.5 for OPEN access instructions) the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.