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.
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
