A Clinical Study of BCD-217 (Nurulimab + Prolgolimab) Followed by Anti-PD-1 Compared to Anti-PD-1 Monotherapy as First-Line Treatment in Subjects With Unresectable/Metastatic Melanoma

A Double-Blind Placebo-Controlled Comparative Randomized Clinical Study of the Efficacy and Safety of BCD-217 (Nurulimab + Prolgolimab) Followed by Anti-PD-1 Compared to Anti-PD-1 Monotherapy as First-Line Treatment in Subjects With Unresectable/Metastatic Melanoma

The aim of study is to investigate the efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics of BCD-217 followed by prolgolimab monotherapy versus prolgolimab monotherapy as first-line therapy in subjects with unresectable or metastatic melanoma.

This study is designed as a phase III, randomized, double-blind, placebo-controlled study.

After the stratification procedure, subjects are randomized in a 1:1 ratio into 2 groups:

• BCD-217 + placebo (4 doses) → prolgolimab (BCD-217 group)
• Prolgolimab + placebo (4 doses) → prolgolimab (BCD-100 monotherapy group)

Inclusion Criteria:

1. Signed informed consent and the subject's ability to comply with the requirements of the clinical study protocol;
2. Age ≥18 years at the time of signing the informed consent form;
3. Histologically confirmed melanoma (with available documented evidence of relevant investigations);
4. Untreated unresectable stage III melanoma or untreated metastatic (stage IV) melanoma;
5. Available blocks for histological examination and/or the subject's consent to undergo biopsy ;
6. Consent to the evaluation of the PD-L1 status and BRAF V600 mutation status at a central laboratory;
7. ECOG score 0-1;
8. Life expectancy of at least 12 weeks ;
9. Measurable target tumor lesions (at least 1 lesion) according to RECIST 1.1 criteria , confirmed by central independent reviewer;
10. In subjects of childbearing potential, willingness to use reliable contraceptive measures throughout the study, from the signing of the informed consent form and for additional 24 weeks after the administration of the last dose of the investigational product.

Exclusion Criteria:

1. Indications for radical (surgical, radiation) therapy;

2. A history of previous systemic antitumor therapy for unresectable or metastatic melanoma ;

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

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

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

6. Ocular melanoma;

7. Mucosal melanoma;

8. CNS metastases;

9. Impossibility to determine PD-L1 status and/or BRAF status;

10. Subjects with severe comorbidities, life-threatening acute complications of the primary disease (including massive pleural, pericardial, or peritoneal effusions requiring intervention , pulmonary lymphangitis, bleeding, or organ perforation) at the time of signing the informed consent form;

11. Ongoing concomitant diseases at the time of screening, which increase the risk of severe adverse events during the administration of the study therapy:

    • stable angina, functional class III-IV;
    • unstable angina or a history of myocardial infarction within less than 6 months prior to signing the informed consent form;
    • moderate to severe heart failure (classes III and IV according to NYHA classification);
    • uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg) ;
    • a history of atopic asthma , angioedema;
    • respiratory failure (moderate to severe), grade 3 or 4 chronic obstructive pulmonary 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 an unacceptable risk during the study therapy;

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

13. History of interstitial pulmonary disease or pneumonitis requiring systemic glucocorticoids;

14. The need for glucocorticoid therapy (at >10 mg/day prednisolone equivalent doses) or any other drugs with immunosuppressive effects within 14 days prior to randomization;

15. Hematologic abnormalities :

    • neutrophils <1.5×109/L;
    • platelets <100×109/L;
    • hemoglobin <90 g/L;

16. Renal impairment: creatinine ≥2.5×ULN;

17. Hepatic impairment :

    • total bilirubin ≥3×ULN (except for subjects with Gilbert's syndrome, in whom bilirubin levels should not exceed 50 μmol/L),
    • AP, AST or ALT ≥2.5×ULN (≥5×ULN in case of subjects with liver metastases);

18. Any antitumor treatment within less than 4 weeks or surgery within less than 28 days prior to randomization within the study;

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

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

21. Participation in other clinical studies within less than 30 days prior to randomization and during this clinical study ;

22. Acute infections or activation of chronic infectious diseases or systemic antibacterial therapy within less than 28 days prior to randomization;

23. Active hepatitis B, active hepatitis C (confirmed by PCR), active syphilis, HIV-infection, currently or previously ;

24. Impossibility to administer the investigational product intravenously;

25. Impossibility to administer intravenous contrast agents (including due to hypersensitivity to contrast media);

26. Hypersensitivity to any of the components of BCD-100 or BCD-217;

27. A history of hypersensitivity to monoclonal antibody products;

28. Pregnancy or breastfeeding.