A Study of Neoadjuvant Therapy With BCD-217 (Nurulimab + Prolgolimab) in Patients With Resectable Stage III Skin Melanoma

Inclusion Criteria:

1. Signed informed consent and the subject's ability to comply with the requirements ofthe clinical study protocol;

2. Age ≥ 18 years at the time of signing the informed consent form;

3. Histologically or cytologically confirmed (documented results of relevant studiesare available) resectable stage IIIB/C/D skin melanoma;

4. At least one clinically detectable lymph node accessible for biopsy and not morethan three resectable in-transit metastases . Clinically detectable lymph nodes include:

• Palpable lymph nodes with pathologically confirmed melanoma

• Non-palpable but enlarged (≥15 mm in smallest diameter, RECIST 1.1) lymph nodeswith pathologically confirmed melanoma

5. Subject's consent to a biopsy;

6. Consent to the evaluation of the PD-L1 status and BRAF V600 mutation status ;

7. ECOG score 0-1;

8. Life expectancy of at least 5 years;

9. Willingness of subjects and their sexual partners of childbearing potential to usereliable methods of contraception from the date of signing the informed consent formthroughout the study period and for 24 weeks after the administration of the lastdose of the investigational therapy.

Exclusion Criteria:

1. Ocular melanoma;

2. Mucosal melanoma;

3. Distant metastases;

4. Impossibility of radical resection of the tumor, metastasis and/or involved lymphnodes;

5. Presence of only in-transit transit/satellite metastases without confirmedinvolvement of lymph nodes;

6. Prior therapy with checkpoint inhibitors (e.g. anti-CTLA-4 and/oranti-PD-1/PD-L1/PD-L2 products);

7. Prior therapy with BRAF and MEK protein kinase inhibitors;

8. Prior radiation therapy;

9. Inability to determine BRAF status;

10. Subjects with severe comorbidities, with life-threatening acute complications of theunderlying disease at the time of signing the informed consent form;

11. Current concomitant diseases at the time of screening, which increase the risk ofsevere adverse events during surgery and/or study therapy administration;

• stable angina, functional class III-IV;

• unstable angina or a history of myocardial infarction within less than 6 monthsprior to signing the informed consent form;

• moderate to severe cardiac failure (NYHA classes III and IV);

• uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic bloodpressure >90 mmHg) ;

• a history of atopic asthma , angioneurotic edema;

• respiratory failure (moderate to severe), grade 3 or 4 chronic obstructivepulmonary disease;

• any other concomitant diseases (including, but not limited to, metabolic,hematological, renal, hepatic, pulmonary, neurological, endocrine, cardiac,infectious, gastrointestinal disorders), which expose the subject to anunacceptable risk during surgery or study therapy;

12. Known or suspected systemic autoimmune diseases (including, but not limited to,systemic lupus erythematosus, Crohn's disease, ulcerative colitis (UC), systemicscleroderma, inflammatory myopathy, mixed connective tissue disease, overlapsyndrome, etc.) ;

13. A history of interstitial pulmonary disease or pneumonitis requiring systemicglucocorticoids;

14. The need for glucocorticoid therapy (at >10mg/day prednisolone equivalent doses) orany other drugs with immunosuppressive effects within 6 months prior torandomization;

15. Use of immunostimulants, monoclonal antibodies and/or colony-stimulating factorswithin less than 4 weeks prior to randomization in the study;

16. Hematological abnormalities :

• neutrophils <1.5×109/L;

• platelets <100×109/L;

• hemoglobin <90 g/L;

17. Renal impairment: creatinine ≥1.5×ULN;

18. Hepatic impairment :

• Total bilirubin ≥1.3×ULN (except for subjects with Gilbert's syndrome, in whombilirubin levels should not exceed 50 μmol/L);

• ALP, AST or ALT ≥1.5×ULN;

19. Any surgery within less than 28 days prior to randomization in the study;

20. History of oncological disease, except for radically treated diseases with remissionfor over 5 years prior randomization in this study ;

21. Conditions limiting the subject's ability to comply with the Protocol requirements (in the Investigator's opinion );

22. Participation in other clinical studies within less than 30 days prior torandomization and during this clinical study ;

23. Acute infections or activation of chronic infectious diseases or systemicantibacterial therapy within less than 28 days prior to randomization;

24. Active hepatitis B, active hepatitis C (confirmed by PCR), HIV-infection, currentlyor previously ;

25. Impossibility to administer the investigational product intravenously;

26. Impossibility to administer intravenous contrast agents (including due tohypersensitivity to contrast media);

27. Hypersensitivity to any of the components of BCD-217, prolgolimab or pembrolizumab;

28. A history of hypersensitivity to monoclonal antibody products;

29. Pregnancy or breastfeeding.