NCT06307093已完成1 期
International, Multicenter, Double-blind, Randomized, Comparative Study of the Pharmacokinetics, Safety and Efficacy of RPH-075 and Keytruda® in Patients With Malignant Neoplasms
R-Pharm46 个研究点 分布在 2 个国家目标入组 90 人开始时间: 2023年3月1日最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 90
- 试验地点
- 46
- 主要终点
- Incidence of Adverse Reactions (ARs)
研究概览
简要总结
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.
详细描述
This study will include the following periods:
- 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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);
- •head and neck squamous cell carcinoma: • unresectable (stage III) or metastatic (stage IV) with PD-L1 TPS expression level ≥ 50% with progression during or after platinum-containing chemotherapy of the 1st line (the drug will be used as a therapy of the 2nd line).
- •The Eastern Cooperative Oncology Group (ECOG) score 0-
- •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.
- •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).
- •Life expectancy is at least 12 weeks from the date of randomization (according to the Researcher assessment).
- •Body weight: 50 to 100 kg.
- •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).
排除标准
- •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.
- •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.
- •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.
- •Hematological disorders:
- •neutrophils < 1.5 x 10^9 /L,
- •platelets < 100 x 10^9 /L,
- •hemoglobin < 90 g/L.
- •Renal dysfunction:
- •creatinine > 1.5 × Upper limit of normal (ULN) or glomerular filtration rate < 45 ml/min.
- •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
- •Conducting surgical treatment less than 28 days, radiation therapy less than 14 days before the expected date of randomization into the study.
- •Uveal melanoma or melanoma of the mucous membranes.
- •Possibility of radical removal of all metastatic foci.
- •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)
- •Previous therapy with pembrolizumab and other anti- Programmed cell death 1 (PD-1)/PD-L1/Programmed Cell Death 1 Ligand 2 (PD-L2) drugs.
- •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 carcinoma of the skin.
- •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.).
- •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).
- •Acute infectious diseases or activation of chronic infectious diseases less than 28 days before the expected date of randomization into the study.
- •Active hepatitis B, hepatitis C, human immunodeficiency viruses (HIV) infection.
- •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).
- •History of interstitial lung disease (non-infectious nature)/pneumonitis requiring the use of steroid therapy, current pneumonitis/Interstitial lung disease (ILD).
- •Impossibility of intravenous administration of the study drug.
- •Impossibility of intravenous contrast.
- •Hypersensitivity (grade 3 or more) to any of the components of the drug RPH-075/Keytruda®.
- •History of hypersensitivity to monoclonal antibody drugs.
- •Pregnancy or breastfeeding.
- •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.
研究组 & 干预措施
RPH-075
Experimental
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.
干预措施: RPH-075 (Drug)
Keytruda®
Active Comparator
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.
干预措施: Keytruda® (Drug)
结局指标
主要结局
Incidence of Adverse Reactions (ARs)
时间窗: 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
时间窗: 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.
次要结局
- 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)
研究者
研究点 (46)
Loading locations...
相似试验
已完成
1 期
A Study to Assess the PK, PD, Safety and Immunogenicity of Single IV Infusion of BCD-264 and Darzalex in Healthy SubjectsHealthyNCT05974969Biocad146
已完成
3 期
Study сomparing the Efficacy and Safety of RPH-075 and Keytruda® in Patients With Unresectable or Metastatic Skin MelanomaSkin MelanomaNCT06320353R-Pharm266
已完成
3 期
A Study to Investigate Interchangeability of ABP 654 for the Treatment of Participants With Moderate to Severe Plaque PsoriasisPsoriasisNCT04761627Amgen494
已完成
1 期
Pharmacokinetic Equivalence and Safety Study of RPH-001 and Avastin®HealthyNCT03659305R-Pharm80
已完成
1 期
A PK Study to Compare GME751 (Proposed Pembrolizumab Biosimilar) and US-licensed and EU-authorized Keytruda® in Participants With Stage II and III MelanomaMelanomaNCT06153238Sandoz322