Neoadjuvant and Adjuvant Anti-PD1 or Combinations for Locoregionally Advanced Melanoma

Inclusion Criteria:

• This study is divided into 2 sub-studies/parts designated Part 1 and Part 2 thatwill enroll in sequence starting with Part 1 followed by Part 2. In Part 2, Part 2Cohort A and Part 2 Cohort B will enroll simultaneously. Inclusion criteria apply toPart 1 and Part 2 unless otherwise specified.

• Voluntarily agree to participate by giving signed, dated, and written informedconsent 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 TNMstages (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 refractoryto 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 followinggroups:

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 multipleregional nodal groups, confirmed by pathological diagnosis.

4. Clinically detected single site of nodal metastatic melanoma arising from anunknown primary, confirmed by pathological diagnosis.

5. Participants with in-transit or satellite metastases with or without lymph nodeinvolvement are allowed if they are considered surgically resectable atScreening by the treating surgical oncologist.

6. Participants with distant cutaneous/subcutaneous, soft tissue or nodalmetastases with or without regional lymph node involvement are allowed if theyare considered potentially surgically resectable and can be biopsied atScreening by the treating surgical oncologist. Elevated LDH is not anexclusion.

7. Elevated LDH is not an exclusion.

• Participants are eligible for this study either at presentation for primary melanomawith concurrent regional nodal and/or in-transit or distant metastasis, or at thetime 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, obtainedwithin 90 days from signing informed consent form (ICF). If recent tumor tissue isunavailable or inadequate, a fresh biopsy will be required, unless the principalinvestigator agrees that it is not safe/feasible.

• Participants must be evaluated by standard-of-care full body imaging studies, thechoice of which is decided by the treating physician investigator.

• Women of childbearing potential (WOCBP) must have a negative urine or serumpregnancy test at screening (within 72 hours of first dose of study medication) inaccordance with the standard of care for WOCBP.

• WOCBP must agree to use highly effective contraceptive measures starting with thescreening visit through 5 months after the last dose of study treatment. Highlyeffective contraception is as stipulated in national or local guidelines.

• Male participants with a female partner(s) of childbearing potential must agree touse highly effective contraceptive measures throughout the study starting with thescreening 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 ofcontraception 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 formelanoma within 4 weeks of initiation of study drugs. Patients must not haveradiotherapy within the preceding 2 weeks. Patients must have recovered from adverseevents due to agents administered more than 4 weeks earlier.

• Participants must be at least 4 weeks from major surgery and have fully recoveredfrom 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 vascularaccident/stroke or myocardial infarction within 6 months of enrollment, unstableangina, congestive heart failure or serious uncontrolled cardiac arrhythmiarequiring medication.

• Active or history of brain metastases or leptomeningeal metastases.

• Concurrent malignancy (present during screening) requiring treatment or history ofprior 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 wascompleted at least 2 years before the first dose of study treatment and the patienthas no evidence of disease. Participants with history of prior early-stagebasal/squamous cell skin cancer, low-risk prostate cancer eligible for activesurveillance or noninvasive or in situ cancers who have undergone definitivetreatment at any time are also eligible.

• Treatment with one of the following classes of drugs within the delineated timewindow 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 seriesshould be completed prior to C1D1, when feasible. Booster shot not required butalso must be administered > 7 days from C1D1 or > 7 days from future cycle onstudy.

• Known allergy or hypersensitivity to any of the study drugs or any of the study drugexcipients.

• Any evidence of current interstitial lung disease (ILD) or pneumonitis or a priorhistory 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 withthe requirements of the study.

• Participants with a condition requiring systemic treatment with eithercorticosteroids (> 10 mg daily prednisone equivalent) within 14 days or anotherimmunosuppressive medication within 30 days of the first dose of study treatment.Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg dailyprednisone equivalent, are permitted in the absence of active autoimmune disease.

• Active autoimmune disease or history of autoimmune disease that required systemictreatment within 2 years before starting treatment, i.e., with use ofdisease-modifying agents or immunosuppressive drugs.

• History or current evidence of any condition, co-morbidity, therapy, any activeinfections, 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 isnot in the best interest of the patient to participate, in the opinion of thetreating Investigator.

• Pregnant or breastfeeding or WOCBP who are not willing to employ effective birthcontrol from screening to 5 months after the last dose of study treatment (whicheveris 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 stablehighly active antiretroviral therapy (HAART) with undetectable viral load and normalCD4 counts for at least 6 months prior to study entry are eligible. Serologicaltesting for HIV at screening is not required.

• Known to be positive for hepatitis B virus (HBV) surface antigen, or any otherpositive test for HBV indicating acute or chronic infection. Patients who arereceiving or who have received anti-HBV therapy and have undetectable HBV DNA for atleast 6 months prior to study entry are eligible. Serological testing for HBV atscreening is not required. Known active co-infection with hepatitis B and hepatitisC or with hepatitis B and hepatitis D is an exclusion.

• Known active hepatitis C virus (HCV) as determined by positive serology andconfirmed by polymerase chain reaction (PCR). Patients on or who have receivedantiretroviral 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 notrequired.

• Dependence on total parenteral nutrition.

• Troponin T (TnT) or I (TnI) > 2× institutional ULN. Participants with TnT or TnIlevels 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, theparticipant must undergo a cardiology consultation and cardiac evaluation and beconsidered for treatment, based on a favorable benefit/risk assessment by theInvestigator. When repeat levels within 24 hours are not available, a repeat testshould be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hoursare < 2 × ULN, the participant must undergo a cardiology consultation and cardiacevaluation and be considered for treatment, based on a favorable benefit-riskassessment by the Investigator.

• Left ventricular ejection fraction (LVEF) assessment with documented LVEF < 50% byeither transthoracic echocardiogram (TTE) or multigated acquisition (MUGA) scan (TTEpreferred 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 studyintervention components.