Study of Efficacy and Safety of BCD-217 (Anti-CTLA-4 and Anti-PD-1) Followed By BCD-100 (Anti-PD-1) Versus BCD-100 Monotherapy as First-Line Treatment in Patients With Unresectable or Metastatic Melanoma

International Multicenter Double-Blind Placebo-Controlled Comparative Randomized Trial of Efficacy and Safety of BCD-217 (Anti-CTLA-4 and Anti-PD-1) And BCD-100 (Anti-PD-1) Therapy Compared to BCD-100 Monotherapy as First-Line Treatment in Patients With Unresectable or Metastatic Melanoma

This is a multicenter randomized double-blind placebo-controlled phase II clinical trial. The purpose of this trial is to evaluate efficacy and safety of therapy consisting of BCD-217 (fixed dose combination of anti-CTLA-4 and anti-PD-1 monoclonal antibodies) and sequential BCD-100 (anti-PD-1 monoclonal antibody) versus BCD-100 monotherapy as first-line treatment in patients with treatment-naïve unresectable or metastatic melanoma.

Inclusion Criteria:

1. Signed Informed Consent Form and the subject's ability to follow the Protocol requirements;
2. Age: 18 years and older at the signing of the informed consent;
3. Histologically verified (documented) melanoma;
4. Previously untreated unresectable stage III melanoma or metastatic stage IV melanoma;
5. Available tissue blocks for histological examination or patient's agreement to give biopsy specimens
6. Patient's consent for PD-L1 expression status and BRAF V600 testing;
7. ECOG performance status of 0 or 1;
8. Life expectancy of at least 12 weeks from the screening;
9. At least one RECIST 1.1-defined measurable target lesion confirmed by an independent review;
10. Patients with reproductive potential must agree to practice acceptable methods of birth control throughout the entire trial period, starting from signing the informed consent and up to 24 weeks after the last dose of investigational drug.

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 patient 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 the patients 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 patients 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 patient'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.