Clinical Trial 20904

• Overview

  Study Title:

  A Randomized Phase 2 Trial of Encorafenib + Binimetinib + Nivolumab vs Ipilimumab + Nivolumab in Braf-V600 Mutant Melanoma with Brain Metastases

  Summary:

  This phase II trial compares the effect of encorafenib, binimetinib, and nivolumab versus ipilimumab and nivolumab in treating patients with BRAF- V600 mutant melanoma that has spread to the brain (brain metastases). Encorafenib and binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Ipilimumab and nivolumab are monoclonal antibodies that may interfere with the ability of tumor cells to grow and spread. This trial aims to find out which approach is more effective in shrinking and controlling brain metastases from melanoma.

  Objective:

  To estimate the overall survival (OS) of participants in each treatment arm. To estimate the objective response rate (ORR) (confirmed and unconfirmed, complete and partial responses) per RECIST 1.1 in each treatment arm. c. To estimate the intracranial response rate (ICRR), defined as confirmed and unconfirmed complete and partial response per modified RECIST for brain metastases (mRECIST) as defined in Section 10.4. In addition, the ICRR as defined by modified RANO-BM and iRANO (by centralized review) will also be estimated.To evaluate the duration of response, per RECIST 1.1 and the duration of ICRR per mRECIST, and per RANO-BM (and iRANO) in each treatment arm. To evaluate the toxicity profile of each treatment arm. To evaluate current and emerging radiographic response criteria (modified RECIST 1.1, modified RANO-BM and iRANO) by a retrospective blinded independent centralized review (BICR) of banked images.

• Treatments

  Therapies:

  Therapy (NOS)

  Medications:

  BMS-936558 (Nivolumab); Binimetinib (); Encorafenib (); Ipilimumab (); Nivolumab (Opdivo); Yervoy (Ipilimumab)

• Inclusion Criteria

  Inclusion Criteria:
  • Must have histologically and pathologically confirmed melanoma that has metastasized to the brain. Brain metastases must be symptomatic at baseline,defined as having neurologic symptoms and/or requiring steroids. Leptomeningeal disease is permitted
  • Any primary (cutaneous, acral/mucosal, etc) or unknown origin are permitted, except that participants with uveal primary are not eligible
  • Must have BRAF-V600 mutant melanoma documented by a Clinical Laboratory Improvement Act (CLIA)-certified laboratory
  • Must have an magnetic resonance imaging (MRI) of the brain within 28 days prior to registration and must have central nervous system metastases with at least one measurable brain metastasis >= 0.5 cm in size (per modified RECIST 1.1) that has not been irradiated, or progressed (in the opinion of the treating physician) after prior radiation therapy. Participating sites MUST use MRI slice thickness of => May have measurable or non-measurable extracranial disease. All measurable disease must be assessed within 28 days prior to randomization; all non-measurable disease must be assessed within 42 days prior to randomization.
  • May be receiving corticosteroids for brain metastases at a dose of up to 8 mg of dexamethasone per day (or equivalent). The dose must not have exceeded 8 mg per day for at least 3 days prior to randomization
  • Must have Zubrod performance status => Must have complete history and physical examination within 28 days prior to randomization
  • Must be able to swallow and retain pills
  • Adequate organ function as outlined per protocol
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2B or better
  • Patients 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
  • Patients 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
  • Patients 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
  • Must agree to participate in image banking. Images must be submitted via the Triad System
  • Participants must be offered the opportunity to participate in specimen and blood collections

• Exclusion Criteria

  Exclusion Criteria:
  • 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
  • Must not have had prior radiation therapy within 7 days prior to randomization
  • Must not be planning to require any additional form of systemic anti-tumor therapy for melanoma while on protocol treatment
  • Must not be planning to use hormonal contraceptives
  • Must not have a serious active infection requiring systemic therapy at time of randomization in the opinion of the treating physician
  • Must not have active autoimmune disease that has required treatment in the past 6 months with use of biologic disease modifying agents (.e.g. infliximab, adalimumab). Patients on non-biologic disease modifying agents (e.g. methotrexate) or patients on corticosteroids => Must 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
  • Must not have had adverse events related to encorafenib and/or binimetinib specifically, that required discontinuation of one or both drugs. (Please note this does not apply to other BRAF/MEK inhibitor drugs.)
  • Must not be pregnant or nursing. Women/men of reproductive potential must have agreed to use an effective method of contraception. (NOTE: Patients must agree to not use hormonal contraceptives, as encorafenib can result in decreased concentration and loss of efficacy.) A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate participant chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
  • Other exclusions may apply

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