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

Skin Melanoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT06320353
• Other study ID #: CL01860211
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: September 27, 2023
• Est. completion date: January 2026

Study information

• Verified date: March 2024
• Source: R-Pharm
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 266
• Est. completion date: January 2026
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Melanoma
• Skin Melanoma
• Skin Neoplasms

Intervention

Drug:
• RPH-075
100 mg/4 mL (25 mg/mL) concentrate for solution for infusions in a single-dose vial The required volume (8 ml) of the Drug concentrate solution should be withdrawn from the vials and transferred into an intravenous bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection. (The final concentration of the diluted solution should be between 1 mg/mL to 10 mg/mL.)
• Keytruda®
100 mg/4 mL (25 mg/mL) concentrate for solution for infusions in a single-dose vial The required volume (8 ml) of the Drug concentrate solution should be withdrawn from the vials and transferred into an intravenous bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection. (The final concentration of the diluted solution should be between 1 mg/mL to 10 mg/mL.)

Locations

Country	Name	City	State
Russian Federation	State Budgetary Healthcare Institution of the Arkhangelsk region "Arkhangelsk Clinical Oncological Dispensary"	Arkhangelsk
Russian Federation	The State Autonomous Healthcare Institution of the Sverdlovsk region "Sverdlovsk Regional Oncological Dispensary"	Ekaterinburg	Sverdlovsk Region
Russian Federation	State Budgetary Healthcare Institution "Regional Oncological Dispensary"	Irkutsk
Russian Federation	State Budgetary Healthcare Institution of the city of Moscow "Moscow City Oncological Hospital No. 62 of the Department of Health of the City of Moscow"	Istra	Moscow Region
Russian Federation	Regional budgetary healthcare institution "Ivanovo Regional Oncological Dispensary"	Ivanovo
Russian Federation	Budgetary Healthcare Institution of the Udmurt Republic "Sergey Grigoryevich Primushko Republican Clinical Oncological Dispensary of the Ministry of Health of the Udmurt Republic"	Izhevsk	Udmurt Republic
Russian Federation	Kaluga Region State Budgetary Healthcare Institution "Kaluga Regional Clinical Oncological Dispensary"	Kaluga
Russian Federation	State Autonomous Healthcare Institution "Republican Clinical Oncological Dispensary of the Ministry of Health of the Republic of Tatarstan named after Professor M.Z.Segal"	Kazan	The Republic Of Tatarstan
Russian Federation	State Budgetary healthcare Institution "Kuzbass Clinical Oncological Dispensary named after M.S. Rappoport"	Kemerovo
Russian Federation	Regional Budgetary Healthcare Institution "Kursk Oncological Research and Clinical Center named after G.E. Ostroverkhov"	Kislino	Kursk Region
Russian Federation	State Budgetary Healthcare Institution "Clinical Oncological Dispensary No. 1" of the Ministry of Health of the Krasnodar Territory	Krasnodar	Krasnodar Territory
Russian Federation	Regional State Budgetary Healthcare Institution "Krasnoyarsk Regional Clinical Oncological Dispensary named after A.I. Kryzhanovsky"	Krasnoyarsk
Russian Federation	"Moscow Center for Rehabilitation Treatment" LLC	Moscow
Russian Federation	"Research lab" LLC	Moscow
Russian Federation	Branch Office of "Hadassah Medical Ltd"	Moscow
Russian Federation	Federal State Autonomous Education Insitution of High Education the First Moscow State Medical University named after I.M. Sechenov of Ministry of Healthcare of Russian Federation (Sechenov University)	Moscow
Russian Federation	Federal State Budgetary Institution "N.N. Blokhin National Medical Research Center of Oncology" of the Ministry of Health of the Russian Federation	Moscow
Russian Federation	Medsi Group of Companies JSC	Moscow
Russian Federation	State Budgetary Healthcare Institution of the city of Moscow "City Clinical Oncological Hospital No. 1 of the Department of Health of the City of Moscow"	Moscow
Russian Federation	State Budgetary Institution of healthcare of the city of Moscow "Moscow Multidisciplinary Clinical Center "Kommunarka" of the Department of Healthcare of the City of Moscow"	Moscow
Russian Federation	State Budgetary Healthcare Institution of the Nizhny Novgorod region "Nizhny Novgorod Regional Clinical Oncological Dispensary"	Nizhny Novgorod
Russian Federation	State Budgetary Healthcare Institution of the Novosibirsk region "Novosibirsk Regional Clinical Oncological Dispensary"	Novosibirsk
Russian Federation	Federal State Budgetary Institution "National Medical Research Center of Radiology" of the Ministry of Health of the Russian Federation	Obninsk	Kaluga Region
Russian Federation	Budgetary healthcare institution of the Omsk region "Clinical Oncological Dispensary"	Omsk
Russian Federation	State Budgetary Healthcare Institution of the Perm Territory "Perm Regional Oncological Dispensary"	Perm
Russian Federation	The State budgetary healthcare Institution of the Stavropol Territory "Pyatigorsk Interdistrict Oncological Dispensary"	Pyatigorsk	Stavropol Territory
Russian Federation	"Euro Cityclinic" LLC	Saint Petersburg
Russian Federation	Private healthcare institution "Clinical Hospital "Russian Railways-Medicine" of the city of St. Petersburg"	Saint Petersburg
Russian Federation	St. Petersburg State Budgetary Healthcare Institution "City Clinical Oncological Dispensary"	Saint Petersburg
Russian Federation	State Budgetary Healthcare Institution Leningrad Regional Clinical Hospital	Saint Petersburg
Russian Federation	State Budgetary Healthcare Institution "Samara Regional Clinical Oncological Dispensary"	Samara
Russian Federation	State Healthcare Institution "Regional Clinical Oncological Dispensary"	Saratov
Russian Federation	Regional State Budgetary Healthcare Institution "Smolensk Regional Oncological Clinical Dispensary"	Smolensk
Russian Federation	Siberian State Medical University of the Ministry of Healthcare of Russian Federation	Tomsk
Russian Federation	The State Autonomous healthcare Institution of the Tyumen region "Multidisciplinary clinical Medical Center "Medical City"	Tyumen
Russian Federation	State Autonomous Healthcare Institution Republican Clinical Oncological Dispensary of the Ministry of Health of the Republic of Bashkortostan	Ufa	The Republic Of Bashkortostan

Sponsors (4)

Lead Sponsor	Collaborator
R-Pharm	Data Management 365, Exacte Labs LLC, Federal State Budgetary Institution of the Central Research Institute of Epidemiology of Rospotrebnadzor

Country where clinical trial is conducted

Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The objective response rate (ORR)	The objective response rate parameter (ORR) is the percentage of patients in a particular group who experienced a complete or partial tumor response to therapy during treatment, according to the criteria of Response Evaluation Criteria In Solid Tumours (RECIST) 1.1.; The complete response (CR) is the disappearance of all control lesions, confirmed by Computed tomography (CT) data for at least 4 weeks; the short diameter of any lymph node previously considered pathological (control or non-control) should be < 10 mm.; The partial response (PR) is a decrease in the sum of the diameters of the control foci by 30% or more for at least 4 weeks, compared with the initial sum of the diameters of the foci (at screening).	up to 24 weeks
Secondary	The disease control rate (DCR)	DCR is the percentage of patients in a particular group who, during therapy, experienced a complete or partial tumor response to therapy, or disease stabilization, in accordance with RECIST 1.1 criteria.; Stabilization means no decrease in the sum of the diameters of control lesions sufficient to qualify as a PR, or an increase in the sum of diameters of control lesions that can be regarded as disease progression (DP), compared with the smallest sum of diameters recorded during observation.; DP is an increase in the sum of the diameters of control lesions by 20% or more relative to the smallest sum of diameters of control lesions recorded during observation (in this case, its absolute increase should be at least 5 mm), or the appearance of one or more new lesions.	up to 24 weeks
Secondary	The time to response (TTR)	TTR is the time from the start of study therapy to the first documented objective tumor response to therapy, according to RECIST 1.1 criteria.; The complete response (CR) is the disappearance of all control lesions, confirmed by Computed tomography (CT) data for at least 4 weeks; the short diameter of any lymph node previously considered pathological (control or non-control) should be < 10 mm.; The partial response (PR) is a decrease in the sum of the diameters of the control foci by 30% or more for at least 4 weeks, compared with the initial sum of the diameters of the foci (at screening).	from the start of study therapy to the first tumor response to therapy, up to 24 weeks
Secondary	The Duration of response (DOR)	DOR is the time from the first documented objective tumor response to therapy (according to RECIST 1.1 criteria) to disease progression according to RECIST 1.1 criteria or death from any cause.; Disease progression is an increase in the sum of the diameters of control lesions by 20% or more relative to the smallest sum of diameters of control lesions recorded during observation (in this case, its absolute increase should be at least 5 mm), or the appearance of one or more new lesions.; DP is an increase in the sum of the diameters of control lesions by 20% or more relative to the smallest sum of diameters of control lesions recorded during observation (in this case, its absolute increase should be at least 5 mm), or the appearance of one or more new lesions.	from the first tumor response to therapy to the disease progression, up to 24 weeks
Secondary	The Progression-free survival (PFS)	Progression-free survival will be expressed as a level (%) of 6-month PFS. PFS is the time from randomization to disease progression according to RECIST 1.1 criteria or death from any cause. The PFS parameter assessment in this study is based on CT or Magnetic resonance imaging (MRI) data.	up to 12 months