Study сomparing the Efficacy and Safety of RPH-075 and Keytruda® in Patients With Unresectable or Metastatic Skin Melanoma

Inclusion Criteria:

1. A voluntarily signed and dated Informed Consent form (ICF) of the patient.
2. Histologically verified (there are documented results of relevant studies, in theabsence of previous studies results, verification will be performed in the centrallaboratory) skin melanoma (patients with uveal melanoma or melanoma of the mucousmembranes are not included in the study).
3. The following patient populations: with skin melanoma:

• newly diagnosed, previously untreated, unresectable (stage III) or metastatic (stage IV) (the drug will be used as a 1st line therapy);
• unresectable or metastatic, with progression during or after systemic antitumortherapy of the 1st line (the drug will be used as a therapy of the 2nd line);
• with progression after previously performed neoadjuvant /adjuvant therapy,provided that the therapy was completed in a time exceeding 5 half-lives of thedrug used, before randomization (the drug will be used as a 1-line therapy);

4. The Eastern Cooperative Oncology Group (ECOG) score 0-2.
5. The presence of measurable control tumor foci (at least 1 focus), according to theResponse evaluation criteria in solid tumors (RECIST) 1.1, confirmed by the conclusionof the Blinded Independent Central Response Assessment Committee.
6. Absence or resolution of toxic effects of previous therapy or negative consequences ofsurgical operations up to ≤ 2 grade according to Common Terminology Criteria forAdverse Events (CTCAE) 5.0, with the exception of chronic / irreversible adverseevents that do not affect the safety parameters of the studied therapy (for example,alopecia).
7. Life expectancy is at least 12 weeks from the date of randomization (according to theResearcher assessment).
8. Consent of female participants capable of childbirth, defined as all women with thephysiological ability to conceive (with the exception of women with the finalcessation of menstruation, which should be determined retrospectively after 12 monthsof natural amenorrhea, i.e. amenorrhea with an appropriate clinical status, forexample, a suitable age), to use highly effective methods of contraception, startingwith from the moment of signing the informed consent form and throughout the study (for at least 28 days after the last infusion of pembrolizumab) as well as thepresence of a negative pregnancy test result (chorionic gonadotropin test). Consent ofsexually active male participants in a clinical trial to use highly effective methodsof contraception, starting from the moment of signing the informed consent form andthroughout the study (for at least 28 days after the last infusion of pembrolizumab).

Exclusion Criteria:

1. Severe concomitant diseases, with life-threatening, acutely developing complicationsof the underlying disease (including massive pleural, pericardial or peritonealeffusion requiring aspiration, requiring intervention, pulmonary lymphangitis).
2. Metastases in the central nervous system, progressing or accompanied by clinicalsymptoms (for example, cerebral edema, spinal cord compression) or requiring the useof glucocorticosteroids (GCS) and/or anticonvulsants in doses specified in criterionNo. 6; Patients with brain metastases can be included in the study if they receiveadequate therapy (surgery or radiotherapy) and are stabilized by imaging studies forat least 4 weeks before the expected date of randomization into the study.
3. Concomitant diseases that are ongoing at the time of the screening examination andthat increase the patient's risk of developing adverse events during the use of studytherapy:

• stable exertional angina of functional class III-IV, unstable angina, or ahistory of myocardial infarction suffered less than 1 month before the expecteddate of randomization into the study;
• clinically significant rhythm disturbances (patients with asymptomatic atrialfibrillation can be included in the study provided the ventricular rhythm iscontrolled);
• chronic heart failure of classes III-IV according to the New York HeartAssociation (NYHA) classification;
• uncontrolled arterial hypertension (systolic blood pressure above 150 mmHg ordiastolic blood pressure above 90 mmHg during antihypertensive therapy);
• severe respiratory failure;
• any other concomitant disease or condition that significantly increases the riskof developing adverse event (AE) during the study, in the opinion of theInvestigator.

4. Systemic autoimmune diseases in the active phase (including, but not limited to:systemic lupus erythematosus (SLE), Crohn's disease, ulcerative colitis (UC), systemicscleroderma, inflammatory myopathy, mixed forms of connective tissue diseases, overlapsyndrome, etc.), requiring systemic therapy for 2 years before expected date ofrandomization into the study.
5. Endocrine disorders that cannot be compensated for by regular hormone replacementtherapy or other standard therapy at a constant dose for 28 days before the expecteddate of randomization into the study.
6. The need for therapy with GCS and any other drugs that have an immunosuppressiveeffect (at a dose equivalent to the daily use of prednisolone at a dose of >10 mg);the use of inhaled/topical drugs GCS is allowed; patients receiving Janus kinase (JAK)inhibitor therapy for coronavirus infection can be included in the study provided thatJAK inhibitor therapy has been completed for at least 1.5 months. Beforerandomization, patients treated with anti-IL-6 drugs can be included in the study,provided that at least 5 half-lives of the anti-Interleukin 6 (IL-6) drug have passedbefore the expected date of randomization into the study.
7. Hematological disorders:

• neutrophils < 1.5 x 10^9 /L,
• platelets < 100 x 10^9 /L,
• hemoglobin < 90 g/L.

8. Renal dysfunction: • creatinine > 1.5 × Upper limit of normal (ULN) or glomerular filtration rate < 45ml/min.
9. Impaired liver function :

• bilirubin ≥ 1.5 × ULN (except for patients with Gilbert's syndrome, whose totalbilirubin values should not exceed 50 mmol/L),
• Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) ≥ 2.5 × ULN (5 × ULN for patients with liver metastases),
• Alkaline phosphatase ≥ 5 × ULN

10. Conducting surgical treatment less than 28 days, radiation therapy less than 14 daysbefore the expected date of randomization into the study.
11. Uveal melanoma or melanoma of the mucous membranes.
12. Possibility of radical removal of all metastatic foci.
13. Conducting 2 or more lines of systemic antitumor therapy for the underlying disease. (Prior therapy with targeted drugs (Serine/threonine-protein kinase B-raf (BRAF)/Mitogen-activated protein kinase (MEK) inhibitors, c-KIT (CD117) inhibitors) isallowed as 1st line therapy)
14. Previous therapy with pembrolizumab and other anti- Programmed cell death 1 (PD-1)/PD-L1/Programmed Cell Death 1 Ligand 2 (PD-L2) drugs.
15. The presence of another oncological pathology that is progressing or requiresantitumor therapy (including hormonal) within 5 years before signing the ICF, with theexception of radically removed cervical carcinoma in situ, radically removed breastcancer in situ or radically removed basal cell/ squamous cell skin carcinoma.
16. Conditions that limit the patient's ability to comply with the requirements of theprotocol (dementia, neurological or psychiatric disorders, drug and alcohol addiction,etc.).
17. Concurrent participation in other interventional clinical trials, participation inother clinical trials less than 30 days before signing the ICF (provided the patienthas received at least one administration of experimental therapy), as well as previousparticipation in this clinical trial (provided the patient has received at least oneadministration of the drug RPH-075).
18. Acute infectious diseases or activation of chronic infectious diseases less than 28days before the expected date of randomization into the study.
19. Active hepatitis B, hepatitis C, human immunodeficiency viruses (HIV) infection.
20. Therapy with live vaccines during the period 30 days before the expected date ofrandomization into the study. For patients receiving therapy with approvedsevere-acute-respiratory-syndrome-related coronavirus 2 (SARS-CoV2) vaccines,instructions for use and/or local requirements should be followed. The use of theSputnik V vaccine is acceptable, provided that at least 7 days have passed from themoment of administration of the second component of the vaccine to the firstadministration of the study drug).
21. History of interstitial lung disease (non-infectious nature)/pneumonitis requiring theuse of steroid therapy, current pneumonitis/Interstitial lung disease (ILD).
22. Impossibility of intravenous administration of the study drug.
23. Impossibility of intravenous contrast.
24. Hypersensitivity (grade 3 or more) to any of the components of the drugRPH-075/Keytruda®.
25. History of hypersensitivity to monoclonal antibody drugs.
26. Pregnancy or breastfeeding.
27. The presence of any other significant concomitant diseases or conditions that could,in the reasonable opinion of the study physician, adversely affect the patient'sparticipation and well-being in the study and/or distort the evaluation of the studyresults.