Clear Me: Interception Trial to Detect and Clear Molecular Residual Disease in Patients With High-risk Melanoma

Inclusion Criteria:

1. Age ≥ 18 years at the time of screening or age of consent according to law.

2. Written informed consent and any locally required authorization (e.g., data privacy)obtained from the subject prior to performing any protocol-related procedures,including screening evaluations.

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

4. Must have a life expectancy of at least 12 weeks.

5. Histologically confirmed cutaneous or mucosal melanoma.

6. High risk melanoma subjects with disease staging for which adjuvant immunotherapyhas been proven to reduce the risk of relapse versus observation (disease stage: 2B, 2C, 3A, 3B, 3C, 3D, 4 fully resected).

7. Archival tumor formalin-fixed, paraffin-embedded (FFPE) specimens for correlativebiomarker studies are required (1 H&E and 10 unstained 5 microns slides). If surgeryis going to be performed after signing consent, then tumor FFPE from that surgery isallowed.

8. Patient is a candidate for definitive treatment: including surgery, andpost-operative adjuvant immunotherapy with or without radiation for local control.

9. No detectable disease via imaging (CT scan, MRI, with or without Positron emissiontomography (PET) CT scan). Table 4.1.2-1 : Criteria for adequate organ and Marrowfunction

10. Females of childbearing potential who are sexually active with a non-sterilized malepartner must use at least one highly effective method of contraception (see Section 8.1.1 for definition of females of childbearing potential and for a description ofhighly effective methods of contraception) from screening to 180 days after thefinal dose of study treatment. It is strongly recommended for the male partner of afemale subject to also use male condom plus spermicide throughout this period.Cessation of contraception after this point should be discussed with a responsiblephysician. Periodic abstinence, the rhythm method, and the withdrawal method are notacceptable methods of contraception.

11. Non-sterilized male subjects who are sexually active with a female partner ofchildbearing potential must use a male condom with spermicide from screening to 180days after receipt of the final dose of study treatment. It is strongly recommendedfor the female partner of a male subject to also use a highly effective method ofcontraception throughout this period, as described in Section 8.1.2. In addition,male subjects must refrain from sperm donation while on study and for 180 days afterthe final dose of study treatment.

Exclusion Criteria:

1. Diagnosis of uveal melanoma.

2. Any prior systemic anticancer therapy for melanoma. Any concurrent anticancertreatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is allowed.

3. Evidence of metastatic disease at surgical and radiological staging.

4. History of allogeneic organ transplantation.

5. History of allergic reactions or hypersensitivity attributed to compounds of similarchemical or biologic composition to anti-PD-1 or anti-LAG-3 or any of theirexcipients.

6. History of active primary immunodeficiency.

7. Active autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], immune related diverticulitis [priordiverticulitis in the context of diverticulosis is allowed provided is not active],systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis,hypophysitis, uveitis, etc.]. The following are exceptions to this criterion:

8. Participants with vitiligo or alopecia

9. Participants with hypothyroidism (eg, following Hashimoto syndrome) stable onhormone replacement

10. Any chronic skin condition that does not require systemic therapy. Participantswithout active disease in the last 1 year may be included but only afterconsultation with the Principal Investigator

11. Participants with celiac disease controlled by diet alone

12. Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and tuberculosis testing inline with local practice), hepatitis B (known positive Hepatitis B virus (HBV)surface antigen [HBsAg] result), or hepatitis C (HCV). Participants with a past orresolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Participants positive for HCVantibody are eligible only if polymerase chain reaction is negative for HCV RNA.Subjects with well-controlled Human Immunodeficiency Virus (HIV) are allowed.

13. Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension,clinically relevant coronary artery disease or history of myocardial infarction inthe last 4 months or high risk of uncontrolled arrhythmia, active interstitial lungdisease, serious chronic gastrointestinal conditions associated with diarrhea, orpsychiatric illness/social situations that would limit compliance with studyrequirement, substantially increase risk of incurring adverse events (AEs) orcompromise the ability of the participant to give written informed consent.

14. History of another primary malignancy except for:

15. Malignancy treated with curative intent and with no known active disease ≥ 3years before the first dose of study treatment and of low potential risk forrecurrence.

16. Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease.

17. Adequately treated carcinoma in situ without evidence of disease.

18. Participants with a history of prostate cancer (tumor/node/metastasis stage) ofStage ≤ T2cN0M0 without biochemical recurrence or progression and who in theopinion of the investigator are not deemed to require active intervention

19. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 500msecs calculated from three ECGs.

20. Prior nivolumab or relatlimab therapy.

21. Current or prior use of immunosuppressive medication within 14 days before the firstdose of study intervention. The following are exceptions to this criterion (seeSection 4.7.1.1):

22. Intranasal, inhaled, topical steroids, or local steroid injections (eg,intra-articular injection)

23. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day ofprednisone or its equivalent

24. Steroids as premedication for hypersensitivity reactions (eg, CT scanpremedication)

25. Receipt of live attenuated vaccine within 30 days prior to the first dose of studyintervention. Note: Participants should not receive live vaccine whilst receivingstudy intervention and up to 30 days after the last dose of study intervention.Should the participants be deemed candidates for the Monkey pox vaccine, the casewill need to be discussed with the coordinating Principal Investigator.

26. Participation in another clinical study with an investigational product administeredin the last 28 days prior to randomization or concurrent enrollment in anotherclinical study, unless the study is an observational (non-interventional) clinicalstudy or during the follow-up period of an interventional study.

27. Judgment by the investigator that the participant should not participate in thestudy if the participant is unlikely to comply with study procedures, restrictionsand requirements.

28. For women only - currently pregnant (confirmed with positive pregnancy test) orbreastfeeding.

29. Subjects who are unable to willingly provide consent or are unable to comply withthe protocol procedures.