Phase I Clinical Trial to Evaluate the Tolerability and Pharmacokinetics of TQB2868 Injection in Subjects With Advanced Malignant Tumors
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 280
- 试验地点
- 3
- 主要终点
- Dose-limiting toxicity (DLT)
研究概览
简要总结
The TQB2868 protein in this study targeted programmed cell death protein 1 (PD-1) and transforming growth factor-β (TGF-β). The bifunctional fusion protein targets and neutralizes TGF-β in the tumor microenvironment. On the basis of inhibiting PD-1 / programmed death ligand 1 (PD-L1) pathway, T cells can restore activity, enhance immune response, and more effectively improve the effect of inhibiting tumor occurrence and development.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1 Subjects voluntarily join the study and sign an informed consent form.
- •2 Age: 18-75 years old (when signing the informed consent form); Eastern Cooperative Oncology Group Performance status (ECOG PS) score: 0~1 points.
- •3 Advanced malignant tumors clearly diagnosed by histology or cytology.
- •4 Patients with advanced malignant tumors who have been diagnosed by tissue and/or cytology and have failed standard treatments or lack effective treatment options.
- •5 The main organs are in good function, and the following examination results are good: routine blood examination, biochemical examination, blood coagulation function examination, heart color Doppler ultrasound evaluation.
- •6 Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, contraceptives, or condoms) during the study period and within 6 months after the end of the study; serum pregnancy/urine within 7 days before study entry The pregnancy test is negative and must be a non-lactating subject; male subjects should agree that contraception must be used during the study period and within 6 months after the end of the study period.
排除标准
- •1 Combined diseases and medical history:
- •Has had other malignant tumors within 3 years before the first medication. The following two conditions can be included in the group: other malignant tumors treated with a single operation to achieve disease-free survival (DFS) for 5 consecutive years; cured cervical carcinoma in situ, non-melanoma skin cancer and superficial bladder tumors [ Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor infiltrating basement membrane)];
- •Unrelieved toxic reactions higher than Common Terminology Criteria Adverse Events (CTC AE) level 1 or higher caused by any previous treatment, excluding hair loss;
- •Major surgical treatment, obvious traumatic injury or long-term unhealed wounds or fractures have been received within 28 days before the first medication;
- •Arterial/venous thrombosis occurred within 6 months before the first administration, such as cerebrovascular accident (including temporary ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism;
- •Existence of active pulmonary tuberculosis, history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonia, radiation pneumonia requiring treatment or active pneumonia with clinical symptoms;
- •People who have a history of psychotropic drug abuse and cannot be quit or have mental disorders;
- •Previous recipients of allogeneic bone marrow transplantation or solid organ transplantation.
- •Subjects with any severe and / or uncontrolled disease.
- •2 Tumor-related symptoms and treatment:
- •Have received chemotherapy, radiotherapy or other anti-cancer therapies within 4 weeks before the first medication (the washout period will be calculated from the end of the last treatment); if you have received local radiotherapy in the past, you can join the group if the following conditions are met: End of radiotherapy more than 4 weeks from the start of the study treatment (brain radiotherapy is more than 2 weeks); and the target lesion selected for this study is not in the radiotherapy area; or the target lesion is located in the radiotherapy area, but progress has been confirmed.
- •Received Chinese patent medicine treatment with anti-tumor indications specified in the National Medical Products Administration (NMPA) approved drug instructions within 2 weeks before the first medication;
- •Have previously received immunological double-antibody therapeutic drugs against the same target of TQB2868 injection;
- •Uncontrollable pleural effusion, pericardial effusion or ascites that still needs to be drained repeatedly (investigator's judgment);
- •Known to have spinal cord compression, cancerous meningitis, accompanied by brain metastasis symptoms, or symptom control time less than 2 weeks;
- •3 Research and treatment related:
- •The history of live attenuated vaccine vaccination within 28 days before the first administration or the planned live attenuated vaccine vaccination during the research period;
- •Those who have had severe hypersensitivity reactions after using macromolecular drugs;
- •An active autoimmune disease that requires systemic treatment (such as the use of disease-relieving drugs, corticosteroids, or immunosuppressive agents) occurred within 2 years before the first medication. Alternative therapies (such as thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency, etc.) are not considered systemic treatments;
- •Diagnosed with immunodeficiency or receiving systemic glucocorticoid therapy or any other form of immunosuppressive therapy (dose>10mg/day prednisone or other curative hormones), and continue within 2 weeks of the first administration in use;
- •4 Participated in other anti-tumor drug clinical trials within 4 weeks before the first medication;
- •5 According to the judgment of the researcher, there are situations that seriously endanger the safety of the subjects or affect the completion of the research by the subjects.
研究组 & 干预措施
TQB2868 Injection
The drug was administered once every 3 weeks (administration time window: ± 3 days), the dose of each administration was 1.5-600 mg, and 3 weeks was a treatment cycle until the disease progressed or the investigator judged that it was not suitable to continue the drug use.
干预措施: TQB2868 Injection (Drug)
结局指标
主要结局
Dose-limiting toxicity (DLT)
时间窗: up to 10 months
DLT definition: the subject has the following adverse events related to the test drug within one treatment cycle (21 days) after the first administration. 1. Grade ≥ 3 neutropenia with fever; Grade 4 neutropenia that cannot be recovered within 3 days after symptomatic treatment; Grade 3 anemia that cannot be recovered within 14 days; ≥ Grade 3 thrombocytopenia with bleeding; Other hematological toxicity above grade 4 (inclusive); 2. ≥ Grade 3 non hematological toxicity; Nausea, vomiting, diarrhea, rash and electrolyte disorder that cannot be recovered to grade ≤ 2 within 7 days after symptomatic treatment; Grade 3 general fatigue, fatigue and headache with duration ≥ 7 days; Laboratory examination abnormalities with isolated ≥ grade 3 and significant clinical symptoms; 3. Adverse events related to ≥ grade 3 infusion reaction occurred, and did not return to normal within 6 hours after stopping infusion
Maximum Tolerated Dose (MTD)
时间窗: up to 10 months
Defined as the highest dose when dose-limiting toxicity (DLT) occurred in less than 33% of subjects.
Recommended Phase II Dose (RP2D)
时间窗: up to 10 months
To evaluate RP2D of TQB2868 injection in adult patients with advanced malignant tumors
All adverse events (AE), serious adverse events (SAE), and treatment-related adverse events (TEAEs)
时间窗: up to 17 months
ncidence of all adverse events (AE), serious adverse events (SAE), and treatment-related adverse events (TEAEs)
次要结局
- Time to reach maximum(peak )plasma concentration following drug administration (Tmax)(up to 17 months)
- Maximum (peak) steady-state plasma drug concentration during a dosage interval (Css-max)(up to 17 months)
- Title：The plasma concentration time curve at steady state, from 0 to τ area under curve of time. (AUC0-τ)(up to 17 months)
- Maximum (peak) plasma drug concentration (Cmax)(up to 17months)
- Area under the plasma concentration-time curve from time zero to time t (AUC0-t)(up to 17 months)
- Area under the plasma concentration-time curve from time zero to infinity(AUC0-∞)(up to 17 months)
- Apparent total clearance of the drug from plasma after oral administration (CL/F)(up to 17 months)
- Elimination half-life (t1/2)(up to 17 months)
- Apparent volume of distribution of intravenous infusion(Vss/F)(up to 17 months)
- Elimination rate constant(λ)(up to 17 months)
- Area under the plasma concentration-time curve from time zero to time 24h.( AUC0-24h)(up to 17 months)
- Mean residence time (MRT)(up to 17 months)
- Minimum steady-state plasma drug concentration during a dosage interval (Css-min)(up to 17 months)
- Degree of fluctuation(DF)(up to 17 months)
- Average steady-state plasma drug concentration during multiple-dose administration (Css-avg)(up to 17 months)
- Anti-drug antibodies(ADA)(up to 17 months)
- Receptor Occupancy(RO)(up to 17 months)
- Progression-free survival (PFS)(up to 29 months)
- Overall response rate (ORR)(up to 29 months)
- Disease control rate（DCR）(up to 29 months)
- Duration of Response (DOR)(up to 29 months)
- Overall survival (OS)(up to 29 months)
- PD-L1 expression in tumor tissue(up to 17 months)
- TGF-β expression in blood samples(up to 17 months)