International, Multicenter, Double-blind, Randomized, Comparative Study of the Pharmacokinetics, Safety and Efficacy of RPH-075 and Keytruda® in Patients With Malignant Neoplasms
Overview
- Phase
- Phase 1
- Intervention
- RPH-075
- Conditions
- Skin Melanoma
- Sponsor
- R-Pharm
- Enrollment
- 90
- Locations
- 23
- Primary Endpoint
- Incidence of Adverse Reactions (ARs)
- Status
- Active, Not Recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
The goal of this double-blind, randomized study is to establish the equivalence of pharmacokinetic properties, as well as the comparability of safety, immunogenicity and pharmacodynamics of the drug RPH-075 (international nonproprietary name (INN) is pembrolizumab) in comparison with the drug Keytruda® (INN is pembrolizumab) after a single intravenous injection to patients with malignant neoplasms as a first or second line therapy in a monotherapy regimen.
The main main tasks are:
- To evaluate and compare the pharmacokinetic properties of RPH-075 and Keytruda® after a single intravenous administration of pembrolizumab to patients with malignant neoplasms;
- To evaluate the safety profile of the drug RPH-075 in comparison with the drug Keytruda® when used in patients with malignant neoplasms when used as a 1st or 2nd line therapy in a monotherapy regimen.
This study will also include a comparative assessment of immunogenicity, pharmacodynamic parameters and a pilot evaluation of RPH-075 efficacy.
Detailed Description
This study will include the following periods: 1. Screening period (before 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). In case of significant adverse events (AEs), pembrolizumab therapy may be postponed for up to 12 weeks. Therapy within the Main Study period will continue until (whichever comes first): * 24 weeks (8 cycles); * 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).
Investigators
Eligibility Criteria
Inclusion Criteria
- •A voluntarily signed and dated Informed Consent form (ICF) of the patient.
- •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); squamous non-small cell lung cancer with Programmed death-ligand 1 (PD-L1) expression level ≥ 1% of tumor cells; head and neck squamous cell carcinoma with PD-L1 Tumor Proportion Score (TPS) expression level ≥ 50%.
- •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);
- •with squamous non-small-cell lung cancer:
- •newly identified unresectable (stage III) or metastatic (stage IV) with PD-L1 expression level ≥ 1%, with intolerance to 1st line chemotherapy (the drug will be used as 1st line therapy);
- •unresectable (stage III) or metastatic (stage IV) with PD-L1 expression level ≥ 1 %, with progression against the background of 1st line antitumor therapy (the drug will be used as a 2nd line therapy);
Exclusion Criteria
- •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).
- •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.
- •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.
- •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.
Arms & Interventions
RPH-075
Pembrolizumab will be administered as an intravenous infusion every 3 weeks, at a fixed dose of 200 mg, for 30 minutes (it is permissible, but not desirable, to carry out an infusion in the range from 25 to 40 minutes). Premedication before administration of pembrolizumab is not mandatory.
Intervention: RPH-075
Keytruda®
Pembrolizumab will be administered as an intravenous infusion every 3 weeks, at a fixed dose of 200 mg, for 30 minutes (it is permissible, but not desirable, to carry out an infusion in the range from 25 to 40 minutes). Premedication before administration of pembrolizumab is not mandatory.
Intervention: Keytruda®
Outcomes
Primary Outcomes
Incidence of Adverse Reactions (ARs)
Time Frame: Days: 1 - 22
Incidence of ARs in both treatment groups by system Organ Class or Preferred Term
Area under the curve "concentration-time" (AUC(0-504)) of pembrolizumab
Time Frame: pre-dose on Day 1 and 0, 2, 4, 5, 6, 8, 12, 24, 48, 72, 120, 168, 336, 504 hours post-dose
The area under the pharmacokinetic curve "concentration-time" of pembrolizumab after the first (single) administration, truncated to the second administration, i.e. the point 504 hours in both treatment groups.
Secondary Outcomes
- Incidence of Treatment-Emergent ARs with grade 3 or more(Days: 1 - 168)
- Incidence of serious adverse events (SAEs)(Days: 1 - 743 (up to 28 days after last pembrolizumab administration))
- The proportion of patients (%) who required therapy discontinuation due to AR development(Days: 1 - 715)
- Incidence of Treatment-Emergent AEs with grade 3 or more(Days: 1 - 743 (up to 28 days after last pembrolizumab administration))
- Maximum serum concentration of pembrolizumab at steady state (Сmax ss)(pre-dose on Day 106 (6th administration) and 0, 2, 4, 5, 6, 8, 12, 24, 48, 72, 120, 168, 336, 504 hours post-dose)
- Minimal serum concentration of pembrolizumab at steady state (Сmin ss)(pre-dose on days: 43, 64, 85, 148)
- Area under the curve "concentration-time" of pembrolizumab at steady state (AUCtau ss)(pre-dose on Day 106 (6th administration) and 0, 2, 4, 5, 6, 8, 12, 24, 48, 72, 120, 168, 336, 504 hours post-dose)
- Incidence of Treatment-Emergent Adverse Events (AEs)(Days: 1 - 168)
- Incidence of imARs with grade 3 or more(Days: 1 - 168)
- Maximum Plasma Concentration (Cmax) of pembrolizumab(pre-dose on Day 1 and 0, 2, 4, 5, 6, 8, 12, 24, 48, 72, 120, 168, 336, 504 hours post-dose)
- Incidence of Immune-mediated adverse reactions (imARs)(Days: 1 - 168)
- Incidence of serious adverse reactions (SARs)(Days: 1 - 168)
- The proportion of patients (%) who developed binding antibodies and neutralizing antibodies to pembrolizumab(Days: 1, 22, 64, 106, 148)