To Evaluate the Efficacy and Safety of TQB3728 Tablets in Sequential Maintenance of TQB2450 Injection Therapy in Patients After Sequential or Concurrent Chemoradiation for Locally Advanced Non-small Cell Lung Cancer.

Study Overview
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Brief Summary
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It's a Phase Ib/II clinical trial to evaluate the efficacy and safety of TQB3728 tablets in sequential maintenance TQB2450 injection therapy in patients after sequential or concurrent chemoradiation for locally advanced non-small cell lung cancer. Incidence and severity of adverse events (AEs), the type of dose-limiting toxicity(ies) (DLT[s]) and Recommended phaseII dose(RP2D) were the Phase Ib primary endpoint. Overall response rate (ORR) was the Phase II primary endpoint.

Official Title
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A Randomized, Open Label, Parallel Controlled, Multicenter Phase Ib/II Clinical Trial to Evaluate the Efficacy and Safety of TQB3728 Tablets in Sequential Maintenance of TQB2450 Injection Therapy in Patients After Sequential or Concurrent Chemoradiation for Locally Advanced Non-small Cell Lung Cancer.

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Combination Product: TQB3728 tablets, TQB2450 injection, sequential or concurrent chemoradiation
* Combination Product: TQB3728 tablets, TQB2450 injection, sequential or concurrent chemoradiation
* Combination Product: TQB2450 injection, sequential or concurrent chemoradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Between the ages of 18-75 years (calculated based on the date of signing Informed consent form (ICF) ); male or female; Non resectable stage III non-small cell lung cancer (NSCLC) patients confirmed by histopathological or cytological examination； At least one measurable lesion (based on RECIST 1.1)； Has not received any systematic treatment or targeted radiotherapy for locally advanced non-small cell lung cancer; Eastern cooperative oncology group (ECOG) score 0-1; Estimated survival time ≥ 3 months; The main organs function are normally, meeting following criteria: routine blood tests: hemoglobin (HGB) ≥80g/L (no blood transfusion and blood products within 14 days); absolute neutrophil count (ANC) ≥1.5×109/L; platelets (PLT)≥90×10^9/L. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN. Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal value (ULN);Serum creatinine (CR) ≤ 1.5×ULN or creatinine clearance (CCR) ≥ 60 ml/min. Prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ≤ 1.5×ULN (no anticoagulant therapy); Cardiac ultrasound assessment: left ventricular ejection fraction (LVEF) ≥ 50%. Female participants should have a negative serum pregnancy test within 7 days prior to study enrollment and must be a non-lactating subject; Participants should agree that contraception must be used during the study period and for 6 months after the end of the study. Exclusion Criteria: Comorbidity and medical history: Have had or currently have other malignant tumors within 2 years. The following two conditions can be enrolled: other malignancies treated with a single surgery; cured cervical carcinoma in situ, non-melanoma skin cancer, and superficial bladder tumors [Ta (non-invasive tumors), Tis (carcinoma in situ) and T1 (tumor-invasive basement membrane)]; Pathological types of mixed small cell and non-small cell lung cancer components； Patients with known EGFR/ALK mutations There was Therapeutic toxicity (≥ CTC AE grade 2 infection) Have a history of idiopathic pulmonary fibrosis, organized pneumonia, drug-induced pneumonia, or idiopathic pneumonia Subjects who have received major surgical treatment or obvious traumatic injury within 4 weeks prior to initial administration Tumor related symptoms and treatment Received Antitumor traditional Chinese medicine treatment within 2 weeks before the start of research treatment； Previously received other PD-1/PD-L1/CTLA-4 antibody treatments or immunotherapy; Uncontrolled pleural effusion, pericardial effusion, or ascites that still require repeated drainage; Research treatment related: Subjects who have received the vaccine within 4 weeks prior to the first dose, or is planning to be vaccinated during the study period Individuals with a previous history of severe allergies to macromolecular drugs or severe hypersensitivity reactions after administration of other monoclonal antibodies Existence of any active autoimmune disease or history of autoimmune disease Subjects who have participated in clinical trials of other anti-tumor drugs within 4 weeks before the first dose According to the judgment of the investigator, subjects with concomitant diseases that seriously endanger the safety of the subjects or affect the completion of the study, or subjects with other reasons which are not suitable for inclusion.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TQB3728 tablets+chemoradiation, sequential maintenance with TQB2450 injection<br>TQB3728 tablets combined with sequential or concurrent chemoradiation, 21 days as a treatment cycle. After 4 6 cycles, sequential maintenance therapy of TQB2450 injection. | Combination Product: TQB3728 tablets, TQB2450 injection, sequential or concurrent chemoradiation<br>* TQB3728 is an inhibitor of apoptosis protein. TQB2450 injection is humanized monoclonal antibody to Programmed Cell Death Protein 1 (PD-1).<br>|
| Experimental: TQB3728 tablets+chemoradiation, sequential maintenance with TQB3728 tablets and TQB2450 injection<br>TQB3728 tablets combined with sequential or concurrent chemoradiation, 21 days as a treatment cycle. After 4 6 cycles, sequential maintenance with TQB3728 tablets and TQB2450 injection for 4 cycles. Then sequential maintenance with TQB2450 injection monotherapy； | Combination Product: TQB3728 tablets, TQB2450 injection, sequential or concurrent chemoradiation<br>* TQB3728 is an inhibitor of apoptosis protein. TQB2450 injection is humanized monoclonal antibody to Programmed Cell Death Protein 1 (PD-1).<br>|
| Active Comparator: Sequential or concurrent chemoradiation, sequential maintenance with TQB2450 injection.<br>Sequential or concurrent chemoradiation, 21 days as a treatment cycle. After 4 6 cycles, sequential maintenance with TQB2450 injection； | Combination Product: TQB2450 injection, sequential or concurrent chemoradiation<br>* TQB2450 injection is humanized monoclonal antibody to Programmed Cell Death Protein 1 (PD-1).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) | All adverse medical events that occur after the subject receives the investigational drug evaluated according to the National Cancer Institute standard for common toxic reactions (NCI-CTC) V5.0. | Baseline to 30 days after last administration. | 
| Severity of adverse events (AEs) | All adverse medical events that occur after the subject receives the investigational drug evaluated according to the National Cancer Institute standard for common toxic reactions (NCI-CTC) V5.0. | Baseline to 30 days after last administration. | 
| Dose-limiting toxicity (DLT) | Subjects within 28 days after treatment appear the following toxicity reaction relate to the drug: grade III or above of non-hematological toxicity, grade IV hematological toxicity, neutropenia associated with fever. | Up to 28 days. | 
| Recommended phase II dose (RP2D) | The RP2D defined as the lower dose level to maximum tolerated dose based on the safety profile. | Baseline to 30 days after last administration. | 
| Overall response rate (ORR) | According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, the proportion of subjects whose tumors are evaluated as complete response (CR) and partial response (PR) by subcenter imaging evaluation. It is recorded from the first dose of the drug to disease progression or initiation of a new anticancer treatment. | Baseline to the disease progression, up to two years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to reach maximum plasma concentration (Tmax) | To characterize the pharmacokinetics of TQB3728 by assessment of time to reach maximum plasma concentration. | For single dose, pre-dose, 0.5,1, 2, 3, 4, 8, 24 hours after dose; For multiple dose, pre-dose on day 3, day 5, day 7, day 14 and 0.5, 1, 2, 4, 8, 24, 48, 72 hours after dose on day14. | 
| Peak concentration (Cmax) | Cmax is the maximum plasma concentration of TQB3728 or metabolite(s). | For single dose, pre-dose, 0.5,1, 2, 3, 4, 8, 24 hours after dose; For multiple dose, pre-dose on day 3, day 5, day 7, day 14 and 0.5, 1, 2, 4, 8, 24, 48, 72 hours after dose on day14. | 
| Terminal half-life (t1/2) | Pharmacokinetics parameters to evaluate the half life of TQB3728. | For single dose, pre-dose, 0.5,1, 2, 3, 4, 8, 24 hours after dose; For multiple dose, pre-dose on day 3, day 5, day 7, day 14 and 0.5, 1, 2, 4, 8, 24, 48, 72 hours after dose on day14. | 
| Area under the plasma concentration-time curve from time zero to time t. | To characterize the pharmacokinetics of TQB3728 by assessment of area under the plasma concentration time curve from zero to specific time or infinity. | For single dose, pre-dose, 0.5,1, 2, 3, 4, 8, 24 hours after dose; For multiple dose, pre-dose on day 3, day 5, day 7, day 14 and 0.5, 1, 2, 4, 8, 24, 48, 72 hours after dose on day14. | 
| Maximum (peak) steady-state plasma drug concentration during a dosage interval (Cmax,ss) | Cmax,ss is the steady state maximum concentration of TQB3728. | For single dose, pre-dose, 0.5,1, 2, 3, 4, 8, 24 hours after dose; For multiple dose, pre-dose on day 3, day 5, day 7, day 14 and 0.5, 1, 2, 4, 8, 24, 48, 72 hours after dose on day14. | 
| Minimum steady-state plasma drug concentration during a dosage interval (Cmin,ss) | Cmin,ss is the minimum plasma concentration of TQB3728. | For single dose, pre-dose, 0.5,1, 2, 3, 4, 8, 24 hours after dose; For multiple dose, pre-dose on day 3, day 5, day 7, day 14 and 0.5, 1, 2, 4, 8, 24, 48, 72 hours after dose on day14. | 
| Disease control rate (DCR) | Percentage of subjects achieving CR and PR and stable disease (SD). | Baseline to up to two years. | 
| Duration of Response (DOR) | The period from the subjects first achieving CR or PR to disease progression. | Baseline to up to two years. | 
| Progression-free survival (PFS) at 12 months. | PFS defined as the time from first dose to the first documented progressive disease (PD) or death from any cause. | Up to 12 months. | 
| Progression-free survival at 18 months. | PFS defined as the time from first dose to the first documented progressive disease (PD) or death from any cause. | Up to 18 months. | 
| Progression-free survival. | PFS defined as the time from first dose to the first documented progressive disease (PD) or death from any cause. | Baseline to the disease progression, up to two years. | 
| Overall survival (OS) at 12 months. | OS is defined as the time from the first administration to all-cause death. | Up to 12 months. | 
| Overall survival (OS) at 18 months. | OS is defined as the time from the first administration to all-cause death. | Up to 18 months. | 
| Overall survival (OS) | OS is defined as the time from the first administration to all-cause death. | Baseline to the disease progression, up to two years. |