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A Study to Compare the Administration of Encorafenib + Binimetinib + Nivolumab Versus Ipilimumab + Nivolumab in BRAF-V600 Mutant Melanoma With Brain Metastases

NCT04511013

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study to Compare the Administration of Encorafenib + Binimetinib + Nivolumab Versus Ipilimumab + Nivolumab in BRAF-V600 Mutant Melanoma With Brain Metastases
  • Official Title: A Randomized Phase 2 Trial of Encorafenib + Binimetinib + Nivolumab vs Ipilimumab + Nivolumab in BRAF-V600 Mutant Melanoma With Brain Metastases

Clinical Trial IDs

  • ORG STUDY ID: S2000
  • SECONDARY ID: NCI-2020-05496
  • SECONDARY ID: S2000
  • SECONDARY ID: S2000
  • SECONDARY ID: U10CA180888
  • NCT ID: NCT04511013

Conditions

  • Acral Lentiginous Melanoma
  • Clinical Stage IV Cutaneous Melanoma AJCC v8
  • Metastatic Cutaneous Melanoma
  • Metastatic Malignant Neoplasm in the Brain
  • Metastatic Melanoma
  • Metastatic Mucosal Melanoma
  • Pathologic Stage IV Cutaneous Melanoma AJCC v8

Interventions

DrugSynonymsArms
BinimetinibARRY-162, ARRY-438162, MEK162, MektoviArm I (encorafenib, binimetinib, nivolumab)
EncorafenibBraftovi, LGX 818, LGX-818, LGX818Arm I (encorafenib, binimetinib, nivolumab)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyArm II (nivolumab, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm I (encorafenib, binimetinib, nivolumab)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid
      Tumors (RECIST) 1.1 between participants randomized to the triplet combination of encorafenib
      + binimetinib + nivolumab versus the doublet combination of ipilimumab + nivolumab among
      participants with BRAF-V600 mutant melanoma that has metastasized to the brain.

      SECONDARY OBJECTIVES:

      I. To estimate the overall survival (OS) of participants in each treatment arm. II. To
      estimate the objective response rate (ORR) (confirmed and unconfirmed, complete and partial
      responses) per RECIST 1.1 in each treatment arm.

      III. To estimate the intracranial response rate (ICRR), defined as confirmed and unconfirmed
      complete and partial response per modified RECIST for brain metastases (mRECIST).

      IV. To evaluate the duration of response, per RECIST 1.1 and the duration of ICRR per
      mRECIST, and per Response Assessment in Neuro-Oncology (RANO)-Brain Metastases (BM) (and
      immunotherapy [i]RANO) in each treatment arm.

      V. To evaluate the toxicity profile of each treatment arm. VI. 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.

      BANKING OBJECTIVE:

      I. To bank tumor tissue, cerebral spinal fluid (CSF), stool and blood samples for future
      correlative studies.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, binimetinib PO
      twice daily (BID) on days 1-28, and nivolumab intravenously (IV) on day 1. Cycles repeat
      every 28 days in the absence of disease progression or unacceptable toxicity.

      ARM II: Patients receive nivolumab IV on day 1 of all cycles and ipilimumab IV over 30
      minutes on day 1 of cycles 1-4. Cycles repeat every 21 days for 4 cycles and then every 28
      days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 6 months for 2 years, and
      then annually until 3 years after randomization.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (encorafenib, binimetinib, nivolumab)ExperimentalPatients receive encorafenib PO QD on days 1-28, binimetinib PO BID on days 1-28, and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Binimetinib
  • Encorafenib
  • Nivolumab
Arm II (nivolumab, ipilimumab)ExperimentalPatients receive nivolumab IV on day 1 of all cycles and ipilimumab IV over 30 minutes on day 1 of cycles 1-4. Cycles repeat every 21 days for 4 cycles and then every 28 days in the absence of disease progression or unacceptable toxicity.
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must have histologically and pathologically confirmed melanoma that has
             metastasized to the brain

          -  Any primary (cutaneous, acral/mucosal, etc) or unknown origin are permitted, except
             that participants with uveal primary are not eligible

          -  Participants must have BRAF-V600 mutant melanoma documented by a Clinical Laboratory
             Improvement Act (CLIA)-certified laboratory

          -  All participants 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 =<
             1.5 mm and are recommended to adhere to the 'minimum' Brain Tumor Imaging Protocol for
             Clinical Trials in Brain Metastases (BTIP-BM) compliant MRI acquisition protocol.
             Computed tomography (CT) of the head cannot substitute for brain MRI. (NOTE: All
             central nervous system [CNS] disease must be documented on BOTH the Brain Metastases
             Baseline Tumor Assessment Form, using modified RECIST, and the Baseline Tumor
             Assessment Form [RECIST 1.1] using RECIST 1.1.)

          -  Participants 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. Please
             note, while any extracranial disease will also be assessed and followed, participants
             are NOT required to have extracranial disease for randomization. NOTE: All disease
             must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1).
             CNS disease must be documented on BOTH the Brain Metastases Baseline Tumor Assessment
             Form, using modified RECIST, and the Baseline Tumor Assessment Form (RECIST 1.1) using
             RECIST 1.1

          -  Participants may have leptomeningeal disease

          -  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

          -  Participants must have Zubrod performance status =< 2

          -  Participants must have complete history and physical examination within 28 days prior
             to randomization

          -  Participants must be able to swallow and retain pills

          -  Hemoglobin >= 8.0 g/dL (within 28 days prior to randomization)

          -  Absolute neutrophil count >= 1,500/mcL (within 28 days prior to randomization)

          -  Platelets >= 75,000/mcL (within 28 days prior to randomization)

          -  Total bilirubin =< 1.5 institutional upper limit of normal (ULN) (within 28 days prior
             to randomization)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
             institutional ULN (in participants with liver metastases =< 5 x ULN) (within 28 days
             prior to randomization)

          -  Creatinine =< 2.0 institutional ULN (within 28 days prior to randomization)

          -  Participants 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

          -  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

          -  Participants 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

          -  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 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

        Exclusion 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

          -  Participants must not have had prior radiation therapy within 7 days prior to
             randomization

          -  Participants must not be planning to require any additional form of systemic
             anti-tumor therapy for melanoma while on protocol treatment

          -  Participants must not be planning to use hormonal contraceptives

          -  Participants must not have a serious active infection requiring systemic therapy at
             time of randomization in the opinion of the treating physician

          -  Participants 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 =< 10 mg prednisone daily or equivalent (to treat
             auto-immune disease), or on replacement therapy (e.g., thyroxine, insulin) are
             eligible if deemed in the best interest of the patient by treating physician

          -  Participants 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

          -  Participants 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.)

          -  Participants 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival
Time Frame:From date of registration to date of first documentation of progression, or symptomatic deterioration, or death due to any cause, assessed up to 3 years after randomization
Safety Issue:
Description:Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:From date of registration to date of death due to any cause, assessed up to 3 years after randomization
Safety Issue:
Description:Will be assessed by Immunotherapy Response Assessment Criteria for Intracranial Metastases (RANO-BM). Will construct Kaplan-Meier plots and estimate the median OS and construct 95% Brookmeyer-Crowley Confidence intervals.
Measure:Intracranial response rate (ICRR)
Time Frame:Up to 3 years after randomization
Safety Issue:
Description:The ICRR is defined as the best response when applying modified (m)RECIST criteria. Will compare intracranial response based on assessments per mRECIST, RANO-BM and immunotherapy (i)RANO criteria based on a review of the banked images. For each of these methods, the best response to treatment will be summarized by treatment arm, the percent agreement between each pair of methods will be reported along with a 95% confidence interval, and a p-value based on a two-sided McNemar's test will be calculated.
Measure:Objective response rate
Time Frame:Up to 3 years after randomization
Safety Issue:
Description:Will be assessed by RECIST 1.1.
Measure:Duration of response
Time Frame:Up to 3 years after randomization
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Southwest Oncology Group

Last Updated

February 25, 2021