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

International, Multicenter, Double-blind, Randomized, Comparative Study of Efficacy and Safety of RPH-075 and Keytruda® in Patients With Unresectable or Metastatic Skin Melanoma

The goal of this double-blind, randomized study is to establish the equivalence of the efficacy, safety and immunogenicity of the drugs RPH-075 (international nonproprietary name (INN) is pembrolizumab) and Keytruda® (INN is pembrolizumab) when used in patients with unresectable or metastatic skin melanoma first or second line therapy in a monotherapy regimen.

The main task is to evaluate and compare the effectiveness of RPH-075 and Keytruda® drugs when used in patients with unresectable or metastatic skin melanoma as a 1 or 2 line therapy in monotherapy regimen, according to the objective response rate (ORR) parameter for up to 24 weeks of therapy.

This study will include the following periods:

1. Screening period (before the first administration of the test drug). Before being included in the study, patients will be provided with complete information about this clinical trial, its objectives, as well as the risks associated with participating in it, as set out in the patient information sheet.

   After the patient signs the Informed consent Form (IF), he will be examined as part of the screening period, at the end of which the researcher will decide whether or not the patient can be randomized into the study.

2. Main period (days: 1 - 168) Patients who meet the selection criteria will be randomized in a 1:1 ratio to one of the two study groups: RPH-075 and Keytruda®.

   Patients will receive pembrolizumab (RPH-075 or Keytruda®) in a monotherapy regimen, at a dose of 200 mg, intravenously, with a frequency of once every 3 weeks (3 weeks - 1 cycle).

   Therapy within the Main Study period will continue until (whichever comes first):

   • 24 weeks (8 cycles, 168 days);
   • disease progression (according to the Immune-Related Response Evaluation Criteria In Solid Tumors (iRECIST)/clinical progression);
   • the development of phenomena of intolerable toxicity.

   The assessment of tumor response to the therapy at this step will be carried out every 12 weeks.

3. Continued therapy period (days: 169 - 365) During the period of continued therapy, all patients will receive therapy with RPH-075, including those patients who received therapy with Keytruda® during the Main Study Period. Pembrolizumab will be administered intravenously, at a dose of 200 mg, with a frequency of once every 3 weeks. In case of significant AEs, pembrolizumab therapy may be postponed for up to 12 weeks.

   Therapy within the period of continued therapy will be carried out until (whichever comes first):

   • a period of up to 1 year;
   • before the disease progression (according to the criteria of iRECIST /clinical progression);
   • the development of phenomena of intolerable toxicity.

   The assessment of tumor response to the therapy at this step will be carried out every 12 weeks.

4. The period of further treatment (days: 366-730]) Participants in this period will be patients who, after 1 year of therapy, will have a stabilization of the disease or a tumor response to therapy. The decision to switch to this period wil be made by the researcher. If, according to the decision of the researcher, the patient will not be recommended to switch to this period, then the patient goes into the Follow-up Period.

   During the the period of further treatment patients will receive therapy with RPH-075 according to the same scheme as in the period of Continued therapy.

   Therapy within the Period will be carried out until (whichever comes first):

   • a total period of up to 2 years; all examinations will be carried out within the framework of routine clinical practice;
   • before the disease progression;
   • the development of phenomena of intolerable toxicity. All examinations necessary for the patient, including radiation diagnostics, and concomitant therapy during the Period will be carried out within the framework of routine clinical practice and through the healthcare system, with the exception of visits where therapy will be administered (every 3 weeks). Also, during these visits, data on the AEs and occurrence of events (progression) will be collected.

5. Follow-up period (FU)

For patients who will have completed their planned participation, namely:

• The period of further treatment,
• The period of continued therapy (those patients who will not be transferred during the pre-treatment Period),

one follow-up visit (FU-visit) will be scheduled 28 ± 3 days after the last administration.

For patients who will complete therapy ahead of schedule (within the Main period or the Period of continued therapy), due to the progression of the disease or the development of intolerant toxicity phenomena, FU visits will be conducted with a multiplicity of 1 every 12 weeks until the Day 365 of the study.

All examinations and concomitant therapy during the Follow-up Period will be provided through the health care system (as a part of routine clinical practice), with the exception of a radiation diagnostic visit conducting to assess the response (every 12 weeks).

The total expected duration of the study is approximately 3 years. The expected duration of participation of each subject is approximately 26 months (about 2 years).

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 the absence of previous studies results, verification will be performed in the central laboratory) skin melanoma (patients with uveal melanoma or melanoma of the mucous membranes 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 antitumor therapy 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 the drug 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 the Response evaluation criteria in solid tumors (RECIST) 1.1, confirmed by the conclusion of the Blinded Independent Central Response Assessment Committee.

6. Absence or resolution of toxic effects of previous therapy or negative consequences of surgical operations up to ≤ 2 grade according to Common Terminology Criteria for Adverse Events (CTCAE) 5.0, with the exception of chronic / irreversible adverse events 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 the Researcher assessment).

8. Consent of female participants capable of childbirth, defined as all women with the physiological ability to conceive (with the exception of women with the final cessation of menstruation, which should be determined retrospectively after 12 months of natural amenorrhea, i.e. amenorrhea with an appropriate clinical status, for example, a suitable age), to use highly effective methods of contraception, starting with 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 the presence of a negative pregnancy test result (chorionic gonadotropin test). Consent of sexually active male participants in a clinical trial to use highly effective methods of contraception, starting from the moment of signing the informed consent form and throughout the study (for at least 28 days after the last infusion of pembrolizumab).

Exclusion Criteria:

1. Severe concomitant diseases, with life-threatening, acutely developing complications of the underlying disease (including massive pleural, pericardial or peritoneal effusion requiring aspiration, requiring intervention, pulmonary lymphangitis).

2. Metastases in the central nervous system, progressing or accompanied by clinical symptoms (for example, cerebral edema, spinal cord compression) or requiring the use of glucocorticosteroids (GCS) and/or anticonvulsants in doses specified in criterion No. 6; Patients with brain metastases can be included in the study if they receive adequate therapy (surgery or radiotherapy) and are stabilized by imaging studies for at 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 and that increase the patient's risk of developing adverse events during the use of study therapy:

   • stable exertional angina of functional class III-IV, unstable angina, or a history of myocardial infarction suffered less than 1 month before the expected date of randomization into the study;
   • clinically significant rhythm disturbances (patients with asymptomatic atrial fibrillation can be included in the study provided the ventricular rhythm is controlled);
   • chronic heart failure of classes III-IV according to the New York Heart Association (NYHA) classification;
   • uncontrolled arterial hypertension (systolic blood pressure above 150 mmHg or diastolic blood pressure above 90 mmHg during antihypertensive therapy);
   • severe respiratory failure;
   • any other concomitant disease or condition that significantly increases the risk of developing adverse event (AE) during the study, in the opinion of the Investigator.

4. Systemic autoimmune diseases in the active phase (including, but not limited to: systemic lupus erythematosus (SLE), Crohn's disease, ulcerative colitis (UC), systemic scleroderma, inflammatory myopathy, mixed forms of connective tissue diseases, overlap syndrome, etc.), requiring systemic therapy for 2 years before expected date of randomization into the study.

5. Endocrine disorders that cannot be compensated for by regular hormone replacement therapy or other standard therapy at a constant dose for 28 days before the expected date of randomization into the study.

6. The need for therapy with GCS and any other drugs that have an immunosuppressive effect (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 that JAK inhibitor therapy has been completed for at least 1.5 months. Before randomization, 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 passed before 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 < 45 ml/min.

9. Impaired liver function :

   • bilirubin ≥ 1.5 × ULN (except for patients with Gilbert's syndrome, whose total bilirubin 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 days before 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) is allowed 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 requires antitumor therapy (including hormonal) within 5 years before signing the ICF, with the exception of radically removed cervical carcinoma in situ, radically removed breast cancer 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 the protocol (dementia, neurological or psychiatric disorders, drug and alcohol addiction, etc.).

17. Concurrent participation in other interventional clinical trials, participation in other clinical trials less than 30 days before signing the ICF (provided the patient has received at least one administration of experimental therapy), as well as previous participation in this clinical trial (provided the patient has received at least one administration of the drug RPH-075).

18. Acute infectious diseases or activation of chronic infectious diseases less than 28 days 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 of randomization into the study. For patients receiving therapy with approved severe-acute-respiratory-syndrome-related coronavirus 2 (SARS-CoV2) vaccines, instructions for use and/or local requirements should be followed. The use of the Sputnik V vaccine is acceptable, provided that at least 7 days have passed from the moment of administration of the second component of the vaccine to the first administration of the study drug).

21. History of interstitial lung disease (non-infectious nature)/pneumonitis requiring the use 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 drug RPH-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's participation and well-being in the study and/or distort the evaluation of the study results.