Inclusion Criteria:
- - This study is divided into 2 sub-studies/parts designated Part 1 and Part 2 that
will enroll in sequence starting with Part 1 followed by Part 2.
In Part 2, Part 2
Cohort A and Part 2 Cohort B will enroll simultaneously. Inclusion criteria apply to
Part 1 and Part 2 unless otherwise specified.
- - Voluntarily agree to participate by giving signed, dated, and written informed
consent prior to any study-specific procedures.
- - 18 years of age or older.
- - Histologic diagnosis of melanoma (cutaneous, acral, mucosal or unknown primary)
belonging to the following American Joint Committee on Cancer (AJCC) 8th edition TNM
stages (Tx or T1-4) and (N1b, N1c, N2b, N2c, N3b or N3c) and/or (M1a).
- - Requirements for prior systemic therapy for melanoma are as follows:
1.
Sub-study Part 1: No prior systemic therapy for melanoma (N=30).
2. Sub-study Part 2 Cohort A: No prior systemic therapy for melanoma (N=20)
3. Sub-study Part 2 Cohort B: Locoregionally advanced melanoma that is refractory
to systemic adjuvant therapy (anti-PD1-based or BRAF-MEK inhibitors) (N=40).
This excludes patients who previously received adjuvant or neoadjuvant anti-PD1 plus
anti-LAG3 or anti-PD1 plus anti-CTLA4.
Participants who experienced progression or recurrence after anti-PD1 as monotherapy or
other combinations or after BRAF-MEK inhibition would be eligible.
Participants who have previously experienced prior high-grade (grade 3 or 4 by CTCAE
criteria) immune related adverse events with immune checkpoint inhibitors are not
eligible.
- - Must be considered surgically operable and may present as any of the following
groups:
1.
Primary melanoma with clinically apparent regional lymph node metastases,
confirmed by pathological diagnosis.
2. Clinically detected recurrence of melanoma at regional lymph node basin(s),
confirmed by pathological diagnosis.
3. Clinically or histologically detected primary melanoma involving multiple
regional nodal groups, confirmed by pathological diagnosis.
4. Clinically detected single site of nodal metastatic melanoma arising from an
unknown primary, confirmed by pathological diagnosis.
5. Participants with in-transit or satellite metastases with or without lymph node
involvement are allowed if they are considered surgically resectable at
Screening by the treating surgical oncologist.
6. Participants with distant cutaneous/subcutaneous, soft tissue or nodal
metastases with or without regional lymph node involvement are allowed if they
are considered potentially surgically resectable and can be biopsied at
Screening by the treating surgical oncologist. Elevated LDH is not an
exclusion.
7. Elevated LDH is not an exclusion.
- - Participants are eligible for this study either at presentation for primary melanoma
with concurrent regional nodal and/or in-transit or distant metastasis, or at the
time of clinically detected nodal, in transit, or distant recurrence.
- - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- - Adequate organ function within 28 days of Cycle 1 Day 1 (C1D1)
- Participants must provide a sufficient and adequate formalin-fixed paraffin-embedded
(FFPE) tumor tissue sample from the most recent biopsy of a tumor lesion, obtained
within 90 days from signing informed consent form (ICF).
If recent tumor tissue is
unavailable or inadequate, a fresh biopsy will be required, unless the principal
investigator agrees that it is not safe/feasible.
- - Participants must be evaluated by standard-of-care full body imaging studies, the
choice of which is decided by the treating physician investigator.
- - Women of childbearing potential (WOCBP) must have a negative urine or serum
pregnancy test at screening (within 72 hours of first dose of study medication) in
accordance with the standard of care for WOCBP.
- - WOCBP must agree to use highly effective contraceptive measures starting with the
screening visit through 5 months after the last dose of study treatment.
Highly
effective contraception is as stipulated in national or local guidelines.
- - Male participants with a female partner(s) of childbearing potential must agree to
use highly effective contraceptive measures throughout the study starting with the
screening visit through 5 months after the last dose of study treatment is received.
Males with pregnant partners must agree to use a condom; no additional method of
contraception is required for the pregnant partner.
- - Willing and able to comply with the requirements of the protocol.
Exclusion Criteria:
- - Pregnancy or lactation.
- - Treatment with another investigational drug or other systemic intervention for
melanoma within 4 weeks of initiation of study drugs.
Patients must not have
radiotherapy within the preceding 2 weeks. Patients must have recovered from adverse
events due to agents administered more than 4 weeks earlier.
- - Participants must be at least 4 weeks from major surgery and have fully recovered
from any effects of surgery and be free of significant detectable infection.
- - Ocular or uveal melanoma.
- - Bowel obstruction or impending bowel obstruction within the past 3 months.
- - Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
accident/stroke or myocardial infarction within 6 months of enrollment, unstable
angina, congestive heart failure or serious uncontrolled cardiac arrhythmia
requiring medication.
- - Active or history of brain metastases or leptomeningeal metastases.
- - Concurrent malignancy (present during screening) requiring treatment or history of
prior malignancy active within 2 years prior to the first dose of study treatment,
i.e., patients with a history of prior malignancy are eligible if treatment was
completed at least 2 years before the first dose of study treatment and the patient
has no evidence of disease.
Participants with history of prior early-stage
basal/squamous cell skin cancer, low-risk prostate cancer eligible for active
surveillance or noninvasive or in situ cancers who have undergone definitive
treatment at any time are also eligible.
- - Treatment with one of the following classes of drugs within the delineated time
window prior to C1D1:
1.
Cytotoxic, targeted therapy or other investigational therapy within 3 weeks.
2. mAbs, antibody-drug conjugates, radioimmunoconjugates, or similar therapy,
within 4 weeks, or 5 half-lives, whichever is shorter.
3. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine or booster
< 7 days before C1D1. For vaccines requiring more than 1 dose, the full series
should be completed prior to C1D1, when feasible. Booster shot not required but
also must be administered > 7 days from C1D1 or > 7 days from future cycle on
study.
- - Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.
- - Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior
history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids.
- - History of allogeneic organ transplant.
- - Psychiatric or substance abuse disorders that would interfere with cooperation with
the requirements of the study.
- - Participants with a condition requiring systemic treatment with either
corticosteroids (> 10 mg daily prednisone equivalent) within 14 days or another
immunosuppressive medication within 30 days of the first dose of study treatment.
Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily
prednisone equivalent, are permitted in the absence of active autoimmune disease.
- - Active autoimmune disease or history of autoimmune disease that required systemic
treatment within 2 years before starting treatment, i.e., with use of
disease-modifying agents or immunosuppressive drugs.
- - History or current evidence of any condition, co-morbidity, therapy, any active
infections, or laboratory abnormality that might confound the results of the study,
interfere with the patient's participation for the full duration of the study, or is
not in the best interest of the patient to participate, in the opinion of the
treating Investigator.
- - Pregnant or breastfeeding or WOCBP who are not willing to employ effective birth
control from screening to 5 months after the last dose of study treatment (whichever
is later).
- - Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or
20 days for severe/critical illness prior to C1D1.
- - Uncontrolled infection with human Immunodeficiency virus (HIV).
Patients on stable
highly active antiretroviral therapy (HAART) with undetectable viral load and normal
CD4 counts for at least 6 months prior to study entry are eligible. Serological
testing for HIV at screening is not required.
- - Known to be positive for hepatitis B virus (HBV) surface antigen, or any other
positive test for HBV indicating acute or chronic infection.
Patients who are
receiving or who have received anti-HBV therapy and have undetectable HBV DNA for at
least 6 months prior to study entry are eligible. Serological testing for HBV at
screening is not required. Known active co-infection with hepatitis B and hepatitis
C or with hepatitis B and hepatitis D is an exclusion.
- - Known active hepatitis C virus (HCV) as determined by positive serology and
confirmed by polymerase chain reaction (PCR).
Patients on or who have received
antiretroviral therapy are eligible provided they are virus-free by PCR for at least
6 months prior to study entry. Serological testing for HCV at screening is not
required.
- - Dependence on total parenteral nutrition.
- - 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 must undergo a cardiology consultation and cardiac evaluation and be
considered for treatment, based on a favorable benefit/risk assessment by the
Investigator. 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 must undergo a cardiology consultation and cardiac
evaluation and be considered for treatment, based on a favorable benefit-risk
assessment by the Investigator.
- - Left ventricular ejection fraction (LVEF) assessment with documented LVEF < 50% by
either transthoracic echocardiogram (TTE) or multigated acquisition (MUGA) scan (TTE
preferred test) within 6 months prior to start of study treatment.
- - Participants with a history of myocarditis and/or current diagnosis of myocarditis,
regardless of etiology.
- - Participants must not have a history of allergy or hypersensitivity to study
intervention components.
