Nivolumab Alone or Plus Relatlimab or Ipilimumab for Patients With Locally-Advanced Unresectable or Metastatic Basal Cell Carcinoma

Inclusion Criteria:

1. Signed Written Informed Consent

2. Subjects must have signed and dated an Institutional Review Board (IRB)-approved written informed consent form in accordance with regulatory andinstitutional guidelines. This must be obtained before the performance of anyprotocol related procedures that are not part of normal subject care.

3. Subjects must be willing and able to comply with scheduled visits, treatmentschedule, laboratory tests, and other requirements of the study.

4. Type of Participant and Target Disease Characteristics

5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.

6. Participants with histologically confirmed Basal Cell Carcinoma with diseasethat is considered by the investigator to be unresectable or metastatic. i) COHORT A: Patients with advanced BCC who are treatment-naïve (i.e., no priorhedgehog pathway inhibitors and T cell modulating agents) will receive anti-PD-1 (nivolumab) alone. ii) COHORT B: • Patients with advanced BCC who experience disease progression onanti-PD-1 (nivolumab) + anti-LAG-3 (relatlimab) will receive anti-PD-1 (nivolumab) +anti-CTLA-4 (ipilimumab). iii) COHORT C: • Patients with advanced BCC who experience disease progression onanti-PD-1 (on or off trial) will receive anti-PD-1 (nivolumab) + anti-LAG-3 (relatlimab). c. At least one measurable lesion by the RECIST 1.1 Criteria. d. Participants with Gorlin syndrome will be permitted to enroll in the study. e. Male or female, aged 18 years or older. f. Patients may not have received prior T cell modulating agents for BCC (e.g.,anti-CTLA-4, anti-PD-L1, anti-LAG-3, anti-KIR, etc.)

7. Laboratory Testing Requirements Screening laboratory values obtained within -28 +/- 3 days of first dose must meetthe following criteria:

8. White Blood Cells greater than or equal to 2000/μL

9. Neutrophils greater than or equal to 1500/μL

10. Platelets greater than or equal to 100 x 10³/μL

11. Hemoglobin greater than or equal to 9.0 g/dL

12. Serum creatinine less than or equal to 1.5 x Upper Limit of Normal (ULN)orcreatinine clearance (CrCl) greater than or equal to 40 mL/minute (usingCockcroft/Gault formula)

13. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less thanor equal to 3 x ULN, except in patients with liver metastases whose values maybe less than or equal to 5 x ULN

14. Total Bilirubin less than or equal to 1.5 x ULN (except subjects with GilbertSyndrome who may have total bilirubin less than or equal to 3.0 mg/dL)

15. Reproductive Status

16. Women of childbearing potential (WOCBP) must have a negative serum or urinepregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the initial administration of study drug, then every 4 weeks +/- 1 week thereafter for the duration of treatment with study drug(s).

17. Women must not be breastfeeding.

18. WOCBP must agree to follow instructions for method(s) of contraception from thetime of enrollment for the duration of treatment with study drug(s) plusapproximately 5 half-lives of study drug(s) plus 30 days (duration of ovulatorycycle) for a total of 5 months post treatment completion.

19. Males who are sexually active with WOCBP must agree to follow instructions formethod(s) of contraception for the duration of treatment with study drug(s)plus approximately 5 half-lives of study drug(s) plus 90 days (duration ofsperm turnover) for a total of 7 months post-treatment completion.

20. Azoospermic males and those who are continuously not heterosexually active areexempt from contraceptive requirements.

21. WOCBP who are continuously not heterosexually active are exempt fromcontraceptive requirements, however they must still undergo pregnancy testingas described in this section.

Exclusion Criteria:

1. Medical Conditions

2. Pregnant or nursing women

3. Central nervous system metastases, unless stable for at least 4 weeks and nolonger requiring steroid therapy.

4. Patients with an autoimmune disease or with a condition requiring systemictreatment with either corticosteroids (> 10 mg daily prednisone equivalent) orother immunosuppressive medications may be permitted to enroll only afterdiscussion with the study P.I.

5. Participants with human immunodeficiency virus (HIV) or acquiredimmunodeficiency syndrome (AIDS).

6. Viral hepatitis. i. Participants with active hepatitis B (positive hepatitis B surface antigen [HBsAg] or hepatitis C virus (HCV) (positive HCV RNA) are excluded. ii. Patients with past Hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and the absence ofHBsAg) are not ineligible, but HBV DNA quantification must be performed and resultsdiscussed with the P.I. iii. HBV carriers or those participants requiring antiviral therapy are not eligibleto participate. iv. Patients positive for HCV antibody are eligible only if polymerase chainreaction (PCR) is negative for HCV RNA after discussion with the study P.I. f. Participants with a prior malignancy active within the previous 2 years may bepermitted to enroll only after discussion with the study P.I. Examples might includelocally curable cancers that have been apparently cured, such as squamous cell skincancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, orbreast. g. Organ transplant recipients with a functioning allograft will be excluded fromthis study. h. For Cohorts B and C, patients may be excluded from the study if they previouslyexperienced a toxicity to immunotherapy that, in the opinion of the investigator,would make it unsafe to restart therapy. Examples may include a Grade 3 or greaterimmune mediated adverse event that was considered related to previous immunotherapyand required immunosuppressive therapy, or an immune mediated adverse event that wasconsidered related to previous immunotherapy and is still > grade 1 despiteadministration of immunosuppressive therapy. Exceptions may include Grade 3ophthalmologic immune-mediated events that improved to Grade 1 within 2 weeks aftertopical therapy only, or Grade 3 endocrine immune-mediated events that did notresult in symptoms lasting >6 weeks and are not requiring >7.5mg prednisone orequivalent per day. i) For Cohort C, Troponin T (TnT) or I (TnI) > 2 × institutional ULN. Participantswith TnT or TnI levels between > 1 to 2 × ULN will be permitted if a repeat levelswithin 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 fortreatment, following cardiologist recommendation. When repeat levels within 24 hoursare not available, a repeat test will be conducted as soon as possible. If TnT orTnI repeat levels beyond 24 hours are < 2 × ULN, the participant may undergo acardiac consultation and be considered for treatment, following cardiologistrecommendation.

7. Allergies and Adverse Drug Reaction

8. History of severe allergy or hypersensitivity to study drug components.

9. Patients with a history of a severe toxicity to an immune checkpoint blockingdrug may be permitted to enroll only after discussion with the study P.I.

10. Other Exclusion Criteria

11. Prisoners or participants who are incarcerated may be permitted to enroll onlyafter discussion with the study P.I.

12. Participants who are detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.