NCT04544748已完成1 期
A Multicenter Open-Label Multi-Cohort Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Immunogenicity of GNR-051 (GENERIUM JSC, Russia) in Subjects With Solid Advanced Malignancies
适应症
干预措施
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- AO GENERIUM
- 入组人数
- 48
- 试验地点
- 24
- 主要终点
- 12-lead electrocardiogram
研究概览
简要总结
It is a Phase 1 Multicenter Open-Label Multi-Cohort Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Immunogenicity of GNR-051 in Subjects with Advanced Solid Malignancies.
详细描述
GNR-051 is a monoclonal antibody, targeting the Programmed Death-1 (PD-1) membrane receptor on T lymphocytes and other cells of the immune system. The anti-PD-1 antibody, preventing the binding of the PD-1 receptor with the ligands PD-L1 and PD-L2, reactivates the pool of tumor-specific cytotoxic T-lymphocytes in the tumor microenvironment and, thus, reactivates the antitumor immunity. GNR-051 is able to block the signaling molecule PD-1, which suppresses the antitumor immune response, for the treatment of cancer.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
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
- •Signed Informed Consent Form and the subject's ability to follow the Protocol requirements;
- •Age: 18 years and older at the signing of the informed consent;
- •Histologically confirmed metastatic solid malignant tumors (non-small cell lung cancer, renal cell carcinoma, melanoma), refractory or recurrent after one or more courses of previous therapy and not subject to surgical treatment and radiation therapy. Melanoma - regardless of the presence and success of previous treatment;
- •ECOG performance status ≤ 2;
- •At least one RESICT 1.1-defined measurable target lesion;
- •Completion of the previous drug treatment of the underlying disease (if applicable) at least 28 days before the first administration of GNR-051;
- •Resolution or stabilization of toxicity manifestations of previous radiation or chemotherapy.
排除标准
- •Prior treatment with anti-CTLA4 and/or anti-PD-1/PD-L1/PD-L2 agents;
- •Hypersensitivity to any of the components of GNR-051;
- •Progression (growth of previous, appearance of new) metastases in the brain and meninges, identified by CT or MRI, in a period of less than 56 days before the first administration of GNR-051; worsening of neurological symptoms in a patient with metastases in the brain or meninges within a period of less than 28 days before the first administration of GNR-051; or continued treatment of metastases in the brain or meninges with glucocorticosteroids (GCS) for a period of less than 14 days before the first administration of GNR-051 (except for a maintenance daily dose of GCS equivalent to 10 mg of prednisolone);
- •Inability to conduct a biopsy according to the protocol;
- •Left ventricular ejection fraction (LVEF) <50% (EchoCG);
- •The need to use anticancer drugs, other than the investigated one, for at least 3 months after the first administration of the drug;
- •Patients who need radiotherapy or surgical therapy;
- •Previous radiotherapy ended <28 days before the first dose administration;
- •Previous stereotactic radiation therapy ended <14 days before the first dose administration;
- •Therapeutic use of radiopharmaceuticals ≤56 days prior to first dose administration;
- •Patients who have received another experimental drug (not registered in Russia) within 28 days or 5 half-lives of the experimental drug before the first administration GNR-051;
- •Patients who have received vaccines against infectious diseases (eg influenza virus) within 28 days before the first administration of the drug;
- •Patients who have received narcotic analgesics <14 days before the first administration of GNR-051;
- •Surgery with general anesthesia <28 days before the first administration of GNR-
- •Surgery with regional / epidural anesthesia <72 hours and / or not all post-anesthetic AEs resolved before the first administration of GNR-051;
- •Laboratory parameters:
- •Absolute leukocyte count <2000 / μL;
- •Absolute neutrophil count <1500 / μL;
- •Absolute platelet count <100 × 103 / μL;
- •Hemoglobin level <9.0 g / dL;
- •Creatinine> 2 mg / dL;
- •AST> 2.5 × the upper limit of normal (ULN) in the absence of liver metastases, or> 5 × ULN with the liver metastases;
- •ALT > 2.5 × ULN in the absence of liver metastases, or> 5 × ULN with the liver metastases;
- •Total bilirubin> 2 × ULN;
- •Systemic autoimmune diseases (including but not limited to SLE, Crohn's disease, ulcerative colitis, systemic scleroderma, inflammatory myopathy, mixed connective tissue disease, overlap syndrome, etc.);
- •Concomitant cancer (except for basal or squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the cervix, prostate, or breast);
- •Patients who need therapy with corticosteroids or other immunosuppressants;
- •Systemic therapy with corticosteroids or immunosuppressants for ≤7 days before the first administration GNR-051;
- •Any other concomitant condition (e.g., medical condition, mental disorders, alcohol/drug abuse) that constitutes an unacceptable risk to the patient's health during the investigational therapy or prevents a patient from following the Protocol procedures;
- •Active HBV/HCV/HIV infection;
- •Pregnant or lactating female;
- •Patients with reproductive potential who do not agree to practice acceptable methods of birth control throughout the entire trial period, starting from signing the informed consent and up to 6 months after the last dose of GNR-051;
- •Simultaneous participation in other clinical trials.
研究组 & 干预措施
Cohort 5
Other
GNR-051 (10 mg/kg)
干预措施: GNR-051 (Biological)
Cohort 1
Other
GNR-051 (0.1 mg/kg)
干预措施: GNR-051 (Biological)
Cohort 2
Other
GNR-051 (0.3 mg/kg)
干预措施: GNR-051 (Biological)
Cohort 3
Other
GNR-051 (1 mg/kg)
干预措施: GNR-051 (Biological)
Cohort 4
Other
GNR-051 (3 mg/kg)
干预措施: GNR-051 (Biological)
结局指标
主要结局
12-lead electrocardiogram
时间窗: 36 Months
Safety profile of GNR-051; All adverse events (CTCAE 5.0)
ECOG assessment
时间窗: 36 Months
Safety profile of GNR-051; All adverse events (CTCAE 5.0)
Antidrug antibody
时间窗: 36 Months
Safety profile of GNR-051; All adverse events (CTCAE 5.0)
Maximum Tolerated Dose (MTD)
时间窗: 28 Days
Tolerability of GNR-051
Number of participants with dose-limiting toxicity (DLT)
时间窗: 28 Days
Tolerability of GNR-051
Laboratory tests
时间窗: 36 Months
Safety profile of GNR-051; All adverse events (CTCAE 5.0)
Physical examination
时间窗: 36 Months
Safety profile of GNR-051; All adverse events (CTCAE 5.0)
Vital signs
时间窗: 36 Months
Safety profile of GNR-051; All adverse events (CTCAE 5.0)
次要结局
- t½ - Half-life after the 1st administration,(6 Months)
- CL - Clearance after the 1st administration(6 Months)
- Accumulation index (Rac; steady-state AUC0-τ/single-dose AUC0-τ)(6 Months)
- Vd, SS - Volume of distribution at steady state(6 Months)
- Progression-Free Survival (PFS)(36 Months)
- Overall Survival (OS)(36 Months)
- Cmax - Maximum serum concentration after the 1st administration(6 Months)
- Cmin - Minimum serum concentration after the 1st administration(6 Months)
- Tmax, SS - Time to peak serum concentration at steady state(6 Months)
- CLSS - Clearance at steady state(6 Months)
- CSS - serum concentration at steady state(6 Months)
- Cmin, SS - serum concentration at steady state(6 Months)
- CAUCτ 0-t - Area under the concentration time-curves from zero to the end of the dosing interval at steady state(6 Months)
- AUC0-∞ - Area under the concentration time-curves from time zero to infinity after last administration(36 Months)
- GNR-051 Serum Concentration(6 Months)
- Tmax - Time to peak serum concentration after the 1st administration(6 Months)
- AUC0-t - Area Under the Curve after the 1st administration(6 Months)
- Time to reach steady state - elimination half-life(6 Months)
- Cmax, SS - Maximum serum concentration at steady state(6 Months)
- t½,ss - Half-life at steady state(6 Months)
- PD-1 receptor occupancy rate (%) in peripheral blood mononuclear cells (PBMCs)(6 Months)
- Best objective response rate (complete response (CR) + partial response (PR))(36 Months)
- Disease Control Rate (DCR)(36 Months)
- Best Overall Response (BOR)(36 Months)
- Objective Response Rate (ORR)(36 Months)
- Duration of response (DoR)(36 Months)
研究者
研究点 (24)
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