A Phase 2 Clinical Trial of Neoadjuvant Relatlimab and Nivolumab in High Risk, Clinical Stage II Cutaneous Melanoma

Inclusion Criteria:

1. The patient (or legally acceptable representative, if applicable) provides written informed consent for the trial.
2. Male/female patients who are at least 18 years of age on the day of signing informed consent.
3. Histologically confirmed primary cutaneous melanoma from a partial core biopsy, punch biopsy, or excisional biopsy with residual macroscopic disease.
4. AJCC (8th edition) clinical stage IIB (T3b and T4a) or IIC (T4b) melanoma, or stage IIA (T2b and T3a) melanoma with a ≥ 20% risk of recurrence at 5 years according to the MIA stage II risk calculator (melanomarisk.org.au).
5. Synchronous primaries are acceptable if there is certainty that a lesion does not represent in-transit disease and consideration should be given to the need for multiple lymph mapping requirements.
6. Past history of a primary melanoma that has been completely excised. If a patient had an SNB, this must be negative.
7. Locoregional, nodal or metastatic spread must be ruled out with clinical examination, dermoscopy, RCM and LC-OCT, CT, MRI (or CT) brain, PET, SPECT/CT and lymphoscintigraphy (including ultrasound of draining nodal basin(s)). Patients with demonstrated clinical stage III melanoma are not eligible.
8. BRAF / NRAS mutant or wild type melanoma included.
9. Availability of the diagnostic tumour sample for translational studies.
10. Surgery has been planned for sentinel node biopsy and complete resection of stage II disease. Only cases where a complete surgical resection leading to tumour free margins and which can be safely achieved without being overly morbid is considered "resectable". Resectability of each case has been agreed upon within the context of a Multi-Disciplinary Team (MDT) meeting.
11. Eastern Cooperative Oncology Group (ECOG) status 0 to 1.
12. Adequate haematological, hepatic, renal and endocrine function on blood pathology testing.
13. Anticipated life expectancy of \>12 months.
14. Agreement to avoid pregnancy for the duration of treatment: Women of childbearing potential (WOCBP) must not be breastfeeding and must have a negative pregnancy test within 3 days prior to initiation of dosing. She 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 plus 5 half-lives of study treatment for a total of 5 months post-treatment completion.

Exclusion Criteria:

1. Clinical or radiographic evidence of nodal, in-transit, satellite or microsatellite metastases or distant melanoma metastases.
2. Any contraindication to the administration of relatlimab or nivolumab.
3. A history of allergy or hypersensitivity to study treatment components.
4. Prior immunotherapy for any malignancy (including, but not limited to: anti-PD-1, CTLA-4, PDL-1 or anti-LAG3 or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways).
5. Patients with a condition requiring chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 14 days prior to the first dose of study treatment. The following are permitted:

   1. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc)
   2. Inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if patient is on a stable dose
   3. Non-absorbed intra-articular steroid injections.
6. Has active autoimmune disease that has required systemic treatment in the past 12 months (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). The following are permitted:

   1. Vitiligo
   2. Type I diabetes mellitus
   3. Residual autoimmune hypothyroidism on stable hormone replacement
   4. Resolved childhood asthma or atopy
   5. Psoriasis not requiring systemic treatment
   6. Autoimmune conditions which are not expected to recur in the absence of an external trigger.
7. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. The following malignancies, if undergone successful definitive resection or curative treatment, are permitted:

   1. Basal cell carcinoma of the skin
   2. Squamous cell carcinoma of the skin
   3. Carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy)
   4. Prostatic intraepithelial neoplasia
   5. Atypical melanocytic hyperplasia
   6. Other malignancies for which the patient has been disease free for 1 year.
8. Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following:

   1. Myocardial infarction or stroke/transient ischemic attack within the 6 months prior to consent
   2. Uncontrolled angina within the 3 months prior to consent
   3. Any history of clinically significant arrhythmias (such as poorly controlled atrial fibrillation, ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
   4. QTc prolongation \> 480 msec
   5. History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, congestive heart failure with New York Heart Association functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion, poorly controlled venous thrombosis, etc)

   (g) Cardiovascular disease-related requirement for daily supplemental oxygen (h) History of 2 or more M.I.s OR 2 or more coronary revascularization procedures (regardless of the number of stent placements during each procedure) (i) Patients with history of myocarditis, regardless of aetiology.
9. 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 enrol the participant following cardiologist recommendation has to be made to the Investigator,
10. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis or current interstitial lung disease.
11. Has an active infection requiring systemic therapy.
12. Treatment with complementary medications (e.g., herbal supplements or traditional Chinese medicines).
13. Any live / live-attenuated vaccine (e.g., varicella, zoster, yellow fever, rotavirus, oral polio and measles, mumps, rubella \[MMR\]) within 30 days of first study treatment, during treatment and until 135 days post last dose. Inactivated / killed vaccines are permitted..
14. Active SARS-CoV-2 infection. The following are permitted

    1. At least 10 days (4 weeks for severe/critical illness) have passed since symptoms first appeared or positive RT-PCR or viral antigen test result.
    2. At least 24 hours have passed since the last fever without the use of fever-reducing medications.
    3. Acute symptoms (e.g., cough, shortness of breath) have resolved.
    4. In the opinion of the investigator, there are no COVID-19-related sequelae that may place the participant at a higher risk of receiving study treatment.
    5. Recommended negative follow-up SARS-CoV-2 RT-PCR or viral antigen test based on institutional / local guidelines.
15. Has a known history of Human Immunodeficiency Virus (HIV). Note: no testing for HIV is required unless mandated by local health authority.
16. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
17. Has a known history of active TB (Bacillus Tuberculosis).
18. Pregnant or breast feeding females.
19. Concurrent medical or social conditions that may prevent the patient from attending assessments per schedule.