Clinical Trial of TQB2868 Injection in Subjects With Advanced Malignant Tumors

Study Overview
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Brief Summary
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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.

Official Title
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Phase I Clinical Trial to Evaluate the Tolerability and Pharmacokinetics of TQB2868 Injection in Subjects With Advanced Malignant Tumors

Conditions
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Advanced Malignant Tumor

Intervention / Treatment
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* Drug: TQB2868 Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TQB2868 Injection<br>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. | Drug: TQB2868 Injection<br>* TQB2868 protein is a bi-functional fusion protein targeting PD-1 and TGF-β<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) | DLT definition: the subject has the following adverse events related to the test drug within one treatment cycle (21 days) after the first administration. 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); ≥ 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; Adverse events related to ≥ grade 3 infusion reaction occurred, and did not return to normal within 6 hours after stopping infusion | up to 10 months | 
| Recommended Phase II Dose (RP2D) | To evaluate RP2D of TQB2868 injection in adult patients with advanced malignant tumors | up to 10 months | 
| Maximum Tolerated Dose (MTD) | Defined as the highest dose when dose-limiting toxicity (DLT) occurred in less than 33% of subjects. | up to 10 months | 
| All adverse events (AE), serious adverse events (SAE), and treatment-related adverse events (TEAEs) | ncidence of all adverse events (AE), serious adverse events (SAE), and treatment-related adverse events (TEAEs) | up to 17 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to reach maximum(peak )plasma concentration following drug administration (Tmax) | To characterize the pharmacokinetics of TQB2868 by assessment of time to reach maximum plasma concentration after single and multiple dosing | up to 17 months | 
| Maximum (peak) plasma drug concentration (Cmax) | Cmax is the maximum plasma concentration of TQB2868. | up to 17months | 
| Maximum (peak) steady-state plasma drug concentration during a dosage interval (Css-max) | Cmax is the steady state maximum concentration of TQB2868 . | up to 17 months | 
| Title：The plasma concentration time curve at steady state, from 0 to τ area under curve of time. (AUC0-τ) | To characterize the pharmacokinetics of TQB2868 by assessment of area under the plasma concentration time curve from the first dose to a certain time point. | up to 17 months | 
| Area under the plasma concentration-time curve from time zero to time t (AUC0-t) | To characterize the pharmacokinetics of TQB2868 by assessment of area under the plasma concentration time curve from the first dose to a certain time point. | up to 17 months | 
| Area under the plasma concentration-time curve from time zero to infinity(AUC0-∞) | To characterize the pharmacokinetics of TQB2868 by assessment of area under the plasma concentration time curve from the first dose to infinity. | up to 17 months | 
| Apparent total clearance of the drug from plasma after oral administration (CL/F) | CL/F is total clearance rate for TQB2868. | up to 17 months | 
| Elimination half-life (t1/2) | t1/2 is time it takes for the blood concentration of TQB2868 to drop by half. | up to 17 months | 
| Apparent volume of distribution of intravenous infusion(Vss/F) | Steady-state apparent volume of distribution of TQB2868 injection by intravenous infusion | up to 17 months | 
| Elimination rate constant(λ) | λ is the elimination rate constant when TQB2868 participates in the calculation of metabolism in the body | up to 17 months | 
| Area under the plasma concentration-time curve from time zero to time 24h.( AUC0-24h) | Characterize the pharmacokinetics of TQB2868 by evaluating the area under the plasma concentration-time curve from the first administration to 24h | up to 17 months | 
| Mean residence time (MRT) | MRT describes the average time that TQB2868 remains in the body. | up to 17 months | 
| Minimum steady-state plasma drug concentration during a dosage interval (Css-min) | Css-min is the minimum plasma concentration of TQB2868. | up to 17 months | 
| Degree of fluctuation(DF) | DF is the volatility coefficient of TQB2868. | up to 17 months | 
| Average steady-state plasma drug concentration during multiple-dose administration (Css-avg) | Css-avg is the average of steady-state plasma concentration of TQB2868 . | up to 17 months | 
| Anti-drug antibodies(ADA) | ADA is antibodies that make TQB2868 clear in the body quickly | up to 17 months | 
| Receptor Occupancy(RO) | RO is a receptor occupancy for TQB2868 involved in metabolism in the body | up to 17 months | 
| Progression-free survival (PFS) | PFS is defined as the time from the first treatment to the first disease progression or death from any cause | up to 29 months | 
| Overall response rate (ORR) | Percentage of participants achieving complete response (CR) and partial response (PR). | up to 29 months | 
| Disease control rate（DCR） | Percentage of participants achieving CR and PR and stable disease (SD). | up to 29 months | 
| Duration of Response (DOR) | The period from the participants first achieving CR or PR to disease progression. | up to 29 months | 
| Overall survival (OS) | OS is defined as the time from the first administration to all-cause death. | up to 29 months | 
| PD-L1 expression in tumor tissue | To evaluate the expression of PD -L1 | up to 17 months | 
| TGF-β expression in blood samples | To evaluate the expression of TGF-β | up to 17 months |