Combined Inhibition of PD-1 and DNA Hypomethylating Agent +/- Chemotherapy in High-risk AML or Elderly Patients With AML Who Are Unfit for Intensive Chemotherapy

Study Overview
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Brief Summary
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This phase II trial studies how well tislelizumab combined with DNA hypomethylation agent +/- CAG regimen (cytarabine, idarubicin / Aclarithromycin, rhG-CSF/ PEG-rhG-CSF) work in treating patients with high-risk acute myeloid leukemia (AML) or AML patients older than 60 years of age who are unfit for standard-dose chemotherapy. The expressions of PD-1 and PD-L1 are increased in AML cells. However, blocking the immune checkpoint alone has limited efficacy as a single agent in highly proliferative leukemia cells. During the recovery period after cytotoxic chemotherapy, the activation of PD-1/PD-L1 pathway may be increased and DNA hypomethylation agents can also up-regulate PD-1, PD-L1 and PD-L2 in AML patients. The up-regulation and activation of above immune checkpoint molecules are related to chemotherapy resistance. Therefore, adding chemotherapy and epigenetic regulation agents to Immune checkpoint blockade therapy may work better through overcoming drug resistance in AML treatment.

Official Title
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A Phase II, Single Arm Study of Tislelizumab Combined With DNA Demethylation Agent +/- CAG Regimen in the Treatment of Patients With High-risk AML or AML Patients Older Than 60 Years of Age Who Are Unfit for Intensive Chemotherapy

Conditions
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Acute Myeloid Leukemia, in Relapsed or Refractory, Acute Myeloid Leukemia, Elderly, Unfit, Acute Myeloid Leukemia With Positive Minimal Residual Disease

Intervention / Treatment
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* Drug: Tislelizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients or their legally authorized representative must provide written informed consent. Meet the diagnostic criteria for acute myeloid leukemia (AML) with positive minimal residual disease (MRD), excluding those patients who are MRD-positive or MRD recurrence after allogeneic hematopoietic stem cell transplantation (HSCT); or meet the diagnostic criteria for relapsed AML, excluding those experience relapsed within 2 months after HSCT from matched sibling donor or within 3 months after HSCT from alternative donor; or meet the diagnostic criteria for refractory AML, excluding those patients within 2 months after HSCT from matched sibling donor or those patients within 3 months after HSCT from alternative donor. Bone marrow (BM) or peripheral blood (PB) leukemia cells were measured to express PD-L1 within 3 months of entering the study. The toxic side effects of the last treatment should be restored. Eastern Cooperative Oncology Group (ECOG) performance status =< 2. Creatinine =< 1.5 x upper limit of normal (ULN). Serum bilirubin =< 1.5 x ULN. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN. Karnofsky Performance Scale Index => 70. The expected survival period is at least 12 weeks. Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (b-hCG) pregnancy test result within 24 hours prior to the first dose of treatment and must agree to use an effective contraception method during the study and for 23 weeks after the last dose of the study drug; females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy. Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 31 weeks following the last dose of study drug. Exclusion Criteria: Patients with positive minimal residual disease (MRD) or MRD recurrence after HSCT; or patients who relapse or refractory within 2 months after HSCT from matched sibling donor or within 3 months after HSCT from alternative donor. History of another primary invasive malignancy that has not been definitively treated or in remission for at least 2 years. Any major surgery, radiotherapy, chemotherapy, biologic therapy, immunotherapy, experimental therapy within 2 weeks prior to the first dose of the study drugs. Patients with any other known concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes; cardiovascular disease including congestive heart failure New York Heart Association [NYHA] class III or IV, myocardial infarction within 6 months, and poorly controlled hypertension; chronic renal failure; or active uncontrolled infection) which, in the opinion of the investigator could compromise participation in the study. Patients unwilling or unable to comply with the protocol. Patients who are on steroids (> 10 mg/day or equivalent) or immune suppression medications. Patients with autoimmune diseases (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's granulomatosis]). Patients with a history of inflammatory bowel disease such as Crohn's disease and ulcerative colitis. Patients known to be positive for hepatitis B surface antigen expression or with active hepatitis C infection (positive by polymerase chain reaction or on antiviral therapy for hepatitis C within the last 6 months), or with known human immunodeficiency virus (HIV) infection. Current therapy with other systemic anti-neoplastic or anti-neoplastic investigational agents. Females who are pregnant or lactating. Any grade of not controlled graft versus host disease.

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: Tislelizumab with DAN hypmethylation agent +/- chemotherapy<br>Decitabine, 20 mg/m2/d, IV, on days 1-5; or Azacitidine, 75 mg/m2/d,SC, on days 1-7. Aclamycin hydrochloride, 20 mg/d, IV, on day 1, 3, and 5 (For relapse/resistance AML, on days 1-5.); or idarubicin hydrochloride,10 mg/d, IV, on day 1, 3, and 5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine,100 mg, IV, q12h/d. For patients with one of the following conditions, cytarabine,10 mg, SC, q12h/d: (1) There are obvious heart, lung, and kidney complications; (2) Bone marrow is hypoproliferative; (3) Age> 75 years old; (4) Age> 60 years old who are unfit for standard-dose chemotherapy. Recombinant human granulocyte colony stimulating factor injection, 5 μg/kg, SC, from day 0 to stop of chemotherapy after the WBC count exceeds 10.0×10^9/L; or Pegylated recombinant human granulocyte stimulating factor injection Liquid, 100 μg/kg, SC, on day 0. Tislelizumab,200 mg, IV, on the next day after chemotherapy was stopped. | Drug: Tislelizumab<br>* Tislelizumab combined with DNA demethylation agent +/- CAG regimen<br>* Other names: Pegylated Recombinant Human Granulocyte Colony Stimulating Factor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | The percentage of subjects with complete remission (CR) and incomplete hematological recovery (CRi) within 2 medication cycles. | Up to 3 months post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of subjects with CR and CRi with negative minimal residual disease (MRD) within 2 cycles. |  | Up to 3 months post-treatment | 
| Duration of Remission (DOR) | The time from first obtaining CR or CRi to relapse or death from AML. | Up to 1 year post-treatment | 
| Progression-free survival time (PFS) | the time from the day of treatment to relapse, progression or death (whichever occurs first is preferred). | Up to 1 year post-treatment | 
| Overall survival (OS) | The time from the day of treatment to death. | Up to 1 year post-treatment | 
| 28-day response rate | The percentage of subjects with CR and CRi (calculated based on the best response) at the 28th day after treatment. | Up to 35 days post-treatment | 
| Incidence of adverse events | The incidence of adverse events will be assessed according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. | Up to 35 days post-treatment | 
| PD-L1 expression in acute myeloid leukemia bone marrow cells | The expression levels of PD-L1 in acute myeloid leukemia bone marrow cells will be assessed at the 28th day after each medication cycle. | Up to 1 year post-treatment |