Clinical Study of TQB2618 Injection in Combination With Demethylation Drugs in Patients With Recurrent/Refractory Acute Myeloid Leukemia, Myelodysplastic Syndromes

Study Overview
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Brief Summary
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This project is an open, dose escalation and expansion phase I clinical study. The first phase is a dose escalation study, and the second phase is a dose expansion study based on the Maximum tolerated dose (MTD) / Recommended Phase II Dose (RP2D) obtained in the first phase. The purpose is to evaluate the tolerability and initially evaluate the antitumor efficacy of TQB2618 injection combined with demethylation drugs in patients with recurrent/refractory acute myeloid leukemia, myelodysplastic syndromes.

Official Title
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Phase I Clinical Study of TQB2618 Injection in Combination With Demethylation Drugs in Patients With Recurrent/Refractory Acute Myeloid Leukemia, Myelodysplastic Syndromes

Conditions
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Recurrent/Refractory Acute Myeloid Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: TQB2618 injection azacitidine, AZA decitabine, DAC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1 Subjects with medium-high risk recurrent/refractory International Prognostic Scoring System (IPSS-R) myelodysplastic syndromes(MDS) and acute myelocytic leukemia(AML) clearly diagnosed by pathology, who were intolerant to other medications and judged by the investigator to have no other appropriate treatment. 2 ≥18 years old; Eastern Cooperative Oncology Group (ECOG) physical status: 0-2; at least 3 months expected survival period. 3 The function of main organs is normal. 4 Subjects must need to adopt effective methods of contraception. 5 Subjects voluntarily joined the study, signed informed consent form, and with good compliance. Exclusion Criteria: 1 Patients has had or is currently having other malignant tumors within 3 years. The following two conditions can be included in the group: other malignant tumors treated with a single operation to achieved 5 consecutive years of disease free survival (DFS)s. Cured cervical carcinoma in situ, non-melanoma skin cancer, nasopharyngeal carcinoma and superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor infiltrating basement membrane)]. 2 Patients diagnosed with acute promyelocytic leukemia or Philadelphia Chromosome-Positive Acute Myeloid Leukemia (Ph+AML) , or low-risk relapsed and refractory AML who only received second-line therapy; 3 The non-hematologic toxicity of previous antitumor treatment is not recovered to ≤ grade 1 (excluding hair loss). 4 Received major surgical treatment, open biopsy or obvious traumatic injury within 4 weeks before treatment. 5 The subjects had any history of bleeding or coagulopathy or who were being treated with anticoagulant. 6 Subjects had an arteriovenous thrombosis event within 6 months. 7 History of drug abuse, alcohol or drug abuse or mental disorder. Subjects who have epilepsy and require treatment. 8 Poor blood pressure control (systolic blood pressure ≥150mmHg or diastolic blood pressure ≥100 mmHg); 9 Subjects who had received allogeneic stem cell transplantation or autologous stem cell transplantation within 3 months； 10 Subjects with ≥ grade 2 myocardial ischemia or infarction, arrhythmia, prolonged QTc interval (including male QTc ≥450ms, female QTc ≥470ms) and ≥ grade 2 congestive heart failure with New York Heart Association (NYHA )classification； 11 Active or uncontrolled severe infection ≥common terminology criteria for adverse events （CTCAE） grade 2 infection)； 12 Subjects with active hepatitis. 13 The subjects was diagnosed with renal failure and required hemodialysis or peritoneal dialysis. 14 History of immunodeficiency, including positive human immunodeficiency virus (HIV) test or other acquired, congenital immunodeficiency disease, or history of organ transplantation. 15 Poor control of diabetes (fasting glucose GLU > 10mmol/L); 16 Subjects who have received radiation therapy or the treatment of proprietary Chinese medicines with anti-tumor indications clearly stated in the National Medical Products Administration (NMPA) approved drug instructions within 4 weeks of starting treatment. 17 Uncontrolled pleural effusion, pericardial effusion or ascites; 18 Subjects with central nervous system aggression; 19 Vaccination history of live attenuated vaccine before 4 weeks of starting treatment, or planned vaccination of live attenuated vaccine during the study period. 20 History of severe allergy to study drugs and pharmaceutical excipients . 21 Subjects diagnosed with active autoimmune disease within 2 years before starting treatment. 22 Receiving any other investigational agent within 4 weeks before first dose. 23 According to the investigator's judgment, there are concomitant diseases that seriously endanger the safety of the subject or affect the completion of the study.

Ages Eligible for Study
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Minimum Age: 18 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: TQB2618 injection<br>TQB2618 injection combined with demethylation drugs, 28 days as a treatment cycle until the disease progresses or the investigator judges that it is not suitable for subject to continue to take medicine. | Drug: TQB2618 injection azacitidine, AZA decitabine, DAC<br>* Drug1: TQB2618 injection is a novel tim-3 inhibitor. Drug2: Azacitidine (5-azacytidine) is a cytidine nucleoside analogue that selectively inhibits DeoxyriboNucleic Acid methyltransferases at low doses, resulting in gene promoter hypomethylation. Drug3: Decitabine is a cytidine deoxy nucleoside analogue that selectively inhibits DNA methyltransferases at low doses, resulting in gene promoter hypomethylation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | To evaluate MTD of TQB2618 injection combined with demethylation drugs in patients with recurrent/refractory acute myeloid leukemia, myelodysplastic syndromes. | Baseline up to 78 weeks | 
| Dose limited toxicity (DLT) | To evaluate DLT of TQB2618 injection combined with demethylation drugs in patients with recurrent/refractory acute myeloid leukemia, myelodysplastic syndromes. | Baseline up to 78 weeks | 
| Recommended Phase II Dose (RP2D) | To evaluate RP2D of TQB2618 injection combined with demethylation drugs in patients with recurrent/refractory acute myeloid leukemia, myelodysplastic syndromes. | Baseline up to 78 weeks | 
| Objective Response Rate | To evaluate ORR of TQB2618 injection combined with demethylation drugs in patients with recurrent/refractory acute myeloid leukemia, myelodysplastic syndromes. | Baseline up to 78 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events (AE) | incidence and severity of adverse events (AE) | Baseline up to 92 weeks | 
| Receptor occupation (RO) | Receptor occupation (RO) of Tim-3 after administration | Baseline up to 92 weeks | 
| anti-drug antibody (ADA)/ neutralizing antibody (Nab) | Immunogenicity related indicators: the incidence and titer of the subjects' anti-drug antibody (ADA) and the incidence of neutralizing antibody (Nab); | Baseline up to 92 weeks | 
| Progress Free Survival (PFS) Progress Free Survival (PFS) | Time from the first dose to the first documentation of progressive disease (PD) or death from any cause, whichever occurs first | up to 92weeks | 
| Disease control rate (DCR) | Percentage of participants achieving complete response (CR) and partial response (PR) and stable disease (SD). | up to 92weeks | 
| Duration of Response (DOR) | The time when the participants first achieved complete or partial remission to disease progression. | up to 92weeks |