Inclusion Criteria:
1. Histologically confirmed non-uveal melanoma that has metastasized to the brain. At
least 1 measurable intracranial target lesion (5-40mm) which was not previously
treated with local therapy (no prior SRS to this lesion). Prior surgery for a brain
metastasis is allowed but this lesion cannot be a target lesion.
a. Growth or change in a lesion previously irradiated will not be considered
measurable. Regrowth in cavity of previously excised lesion will not be considered
measurable.
2. Age ≥ 18 years. 3. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 for Cohort A
(asymptomatic), ECOG performance status 0-2 for Cohort B (symptomatic)
4. No prior anti-CTLA-4, anti-PD-1, or anti-LAG-3 therapy for unresectable stage III/IV
melanoma. Prior CTLA-4, PD-1, and/or LAG-3 therapy in the neoadjuvant or adjuvant
setting is acceptable if >6 months since last treatment. Participants may have had
prior BRAF+MEK inhibitors for adjuvant therapy and/or unresectable/metastatic
melanoma if >2 weeks have elapsed since last treatment.
5. Adequate organ function as assessed by the following parameters:
1. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3
times the upper limit of normal (≤ 3 ×ULN); patients with liver metastasis ≤ 5
× ULN. 2. Estimated creatinine clearance (eCrCl) ≥ 30 mL/min using the Cockcroft-Gault
formula at Screening. 3. Total bilirubin ≤ 1.5x ULN OR direct bilirubin ≤ ULN for participants with
total bilirubin levels >1.5x ULN. 6. Patients must have recovered from all prior anti-cancer therapy-related adverse
events (AEs) to ≤ Grade 1 (per Common Terminology Criteria for Adverse Events
[CTCAE] v 5.0), except for alopecia, vitiligo, thyroid dysfunction, hypophysitis, or
adrenal insufficiency, prior to enrollment.
7. Cohort A (asymptomatic): participants must be free of neurologic signs and symptoms
related to metastatic brain lesions and must not have required or received systemic
corticosteroid therapy greater than physiologic replacement (>10 mg of
prednisone/day or equivalent) in the 10 days prior to beginning protocol therapy.
Cohort B (symptomatic): participants may be on steroids with doses no higher than a
total daily dose of 4 mg of dexamethasone or equivalent that is stable or tapering
within 10 days prior to treatment. Patients who are symptomatic and are not being
treated with steroids are also eligible.
8. 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 treatment.
9. Participants with a known history of hepatitis B virus (HBV) or hepatitis C virus
(HCV) infection must have been treated and cured. Participants with HBV or HCV
infection who are currently on treatment must have an undetectable HCV viral load
prior to treatment.
10. Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin
blocks (blocks are preferred) OR at least 4 unstained slides, with an associated
pathology report, for testing of tumor PD-L1 expression:
1. Tumor tissue should be of good quality based on total and viable tumor content.
2. Patients who do not have tissue specimens may undergo a biopsy during the
screening period. Acceptable samples include core-needle biopsies for deep
tumor tissue or excisional, incisional, punch, or forceps biopsies for
cutaneous, subcutaneous, or mucosal lesions. Fine Needle Aspirations (FNA) will
not be considered acceptable for tissue procurement.
3. Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is
therefore not acceptable.
4. However, if repeat biopsy is not feasible, and no archival tissue available
patient still may be enrolled.
11. Any radiation treatment or excision of non-target brain lesions must have occurred ≥
1 weeks before the start of dosing for this study. NOTE: The radiation field must
not have included the brain index lesion(s).
12. Radiation to non-CNS lesions is allowed and does not require a washout period for
treatment initiation. Any radiation-related toxicity must have recovered to ≤ Grade
1 (per Common Terminology Criteria for Adverse Events [CTCAE] v 5.0).
13. Women of child-bearing potential (WOCBP) must not be breastfeeding and must have a
negative pregnancy test within 3 days prior to initiation of dosing. WOCBP (or
female partners of male participants) must agree to use an acceptable method of
birth control from the time of the negative pregnancy test, through the duration of
treatment with the study combination and for 12 months after their last dose of any
study component medication.
NOTE: A female participant is eligible to participate if she is not a woman of
childbearing potential.
Approved methods of birth control are as follows:
Combined (estrogen and progesterone containing) hormonal birth control associated
with inhibition of ovulation: oral, intravaginal, transdermal Progesterone-only
hormonal birth control associated with inhibition of ovulation: oral, injectable,
implantable Intrauterine device (IUD) Intrauterine hormone-releasing system (IUS)
Bilateral tubal occlusion Vasectomized partner True sexual abstinence when this is
in line with the preferred and usual lifestyle of the patient. Periodic abstinence
(eg, calendar ovulation, symptothermal, post-ovulation methods) is not acceptable. 14. Patients (or legally authorized representative) must have the ability to understand
the requirements of the study, have provided written informed consent as evidenced
by signature on an ICF approved by an Institutional Review Board/Independent Ethics
Committee (IRB/IEC) and agree to abide by the study restrictions and return to the
site for the required assessments.
Exclusion Criteria. 1. Another primary malignancy within the previous 3 years (with the exception of
carcinoma in situ of the breast, cervix, or bladder; localized prostate cancer; and
non-melanoma skin cancer that has been adequately treated).
2. Active medical illness(es) that would pose increased risk for study participation,
including: active systemic infections (including COVID-19), coagulation disorders,
or other major active medical illnesses of the cardiovascular, respiratory, or
immune systems.
3. Active autoimmune disease that has required systemic therapy with corticosteroids or
other immunosuppressive agents within the past 3 years (excluding immune-related
adverse events from immunotherapy as described above.
4. Implanted device that precludes the use of MRI.
5. Prior Grade 4 treatment-related AE with immune checkpoint inhibitor treatment.
6. History of leptomeningeal metastasis determined by imaging or lumbar puncture.
7. Prior whole brain radiation therapy (WBRT)
8. Women who are breast-feeding or pregnant. 9. History of clinically significant cardiac disease or congestive heart failure > New
York Heart Association (NYHA) class 2. Subjects must not have unstable angina
(anginal symptoms at rest) or new-onset angina within the last 3 months or
myocardial infarction within the past 6 months or a history of myocarditis. 10. Troponin T (TnT) or I (TnI) > 2 × institutional ULN. Participants with TnT or TnI
levels between > 1 to 2 × ULN will be permitted if repeat levels within 24 hours are
≤ 1 ULN. If TnT or TnI levels are between >1 to 2 × ULN within 24 hours, the
participant may undergo a cardiac consultation and be considered for treatment,
following cardiologist recommendation. When repeat levels within 24 hours are not
available, a repeat test should be conducted as soon as possible. If TnT or TnI
repeat levels beyond 24 hours are < 2 × ULN, the participant may undergo a cardiac
consultation and be considered for treatment, following cardiologist recommendation.
Notification of the decision to enroll the participant following cardiologist
recommendation has to be made to the principal investigator.
11. Investigational drug use within 14 days (or 5 half-lives, whichever is longer) of
the first dose of study treatment.
12. Dexamethasone use > 4mg/day (or equivalent)
