Clinical Study of the Efficacy and Safety of BCD-263 and Opdivo® As Monotherapy in Subjects with Advanced Melanoma of the Skin

The aim of the study BCD-263-2/UNIVERSE is to demonstrate comparable efficacy and similar safety and immunogenicity profile of BCD-263 and Opdivo after repeated intravenous doses in subjects with advanced unresectable or metastatic melanoma of the skin.

Following screening, subjects will be randomized to receive either BCD-263 or Opdivo in a 1:1 ratio and enter the main study period.

During the main study period, subjects will receive therapy with BCD-263 or Opdivo, which will be administered intravenously until disease progression or signs of unacceptable toxicity develop (whichever occurs earlier).

At Week 25, after completion of all scheduled procedures subjects in both groups will continue to receive open-label BCD-263 for up to a total of 2 years of therapy, or disease progression, or signs of unacceptable toxicity (whichever occurs first).

Following discontinuation of the study therapy, the subjects will enter a follow-up period, during which data on overall survival will be collected through telephone contacts.

Eligibility Criteria:
Inclusion Criteria:

1. Signed informed consent and the subject's ability to comply with the protocol requirements.
2. Age ≥18 years at the time of signing the informed consent form.
3. Histologically confirmed melanoma with the following prognostic characteristics:

   * LDH \<ULN of local laboratory (enrollment of subjects with LDH \<2 x ULN of local laboratory is allowed until the number of subjects with LDH \>ULN is 30% of the total population of randomized subjects. The Sponsor will inform when enrollment of subjects is limited by LDH level \<ULN of the local laboratory).
   * Absence, according to the Investigator, of clinically significant symptoms associated with the tumor.
   * Absence, according to the Investigator, of rapidly progressing metastatic melanoma.
4. Newly diagnosed advanced unresectable (stage III) or metastatic disease (stage IV), or progressive disease during / relapsing after radical treatment.
5. Presence of a tumor sample (archived or new biopsy) that is suitable for evaluation for PD L1 expression in the Investigator's opinion.
6. At least one measurable lesion as per RECIST 1.1 based on independent central review.
7. ECOG score 0-1.
8. Laboratory test results consistent with adequate functioning of systems and organs.

Exclusion Criteria:

1. Indications for radical treatment (surgery, radiation therapy).
2. Uveal or mucosal melanoma.
3. Previous systemic anticancer therapy for advanced unresectable or metastatic skin melanoma.
4. Active CNS metastases and/or carcinomatous meningitis.
5. Previous invasive cancer, excluding diseases treated with potentially radical therapy with no evidence of recurrence for 2 years from the start of this therapy (subjects with radically resected basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, cervical carcinoma in situ of the uterus and other carcinomas in situ may be included).
6. Subjects with severe concomitant disorders, 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 and during the screening period.
7. Concomitant diseases and/or conditions that significantly increase the risk of adverse events (AEs) during the study.
8. Active, known or suspected autoimmune disorders (subjects with type 1 diabetes mellitus or hypothyroidism requiring only hormone-replacement therapy and those with skin disorders \[vitiligo, alopecia, or psoriasis\] not requiring systemic therapy are eligible to participate).
9. The need for systemic corticosteroids (at doses equivalent to \>10 mg/day prednisolone) or any other immunosuppressive drugs within 14 days prior to randomization. The use of inhaled and topical corticosteroids is allowed.
10. History of (non-infectious) pneumonitis requiring corticosteroid therapy or pneumonitis at the time of screening.
11. Any anticancer therapy or major surgery within 28 days prior to randomization, or the subject's AE (other than alopecia) caused by anticancer therapy has not yet recovered to CTCAE grade 1 or has not completely resolved.
12. Concomitant use of drugs or medical devices studied in other clinical studies or their use within 28 days prior to randomization.
13. Infections requiring therapy or systemic antibiotics within 14 days prior to randomization.
14. Administration of a live and/or attenuated vaccine within 28 days prior to randomization.
15. Positive HIV-1 or HIV-2 test.
16. HBV/HCV infections (subjects with a negative PCR result for hepatitis C virus RNA, without significant abnormalities in blood chemistry tests, examined by an infectious disease specialist and not requiring specific antiviral treatment at the time of screening, may be included in the study. Subjects with a positive HbsAg test result cannot be included in the study).
17. Impossibility to administer intravenous contrast agents (including due to hypersensitivity to contrast media).
18. Hypersensitivity or allergy to any of the nivolumab product components. Hypersensitivity or allergy to medicinal products obtained based on Chinese hamster ovary cells, or history of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies or hybrid proteins.
19. Pregnancy or breastfeeding, as well as intention to become pregnant or father a child during the study period.