BLAST MRD AML-2: BLockade of PD-1 Added to Standard Therapy to Target Measurable Residual Disease in Acute Myeloid Leukemia 2- A Randomized Phase 2 Study of Anti-PD-1 Pembrolizumab in Combination With Azacitidine and Venetoclax as Frontline Therapy in Unfit Patients With Acute Myeloid Leukemia

PRIMARY OBJECTIVE:

1. Assess the percentage of patients with minimal residual disease (MRD) negative complete remission (CR) (MRD-CR) or complete remission with incomplete count recovery (MRD-CRi) with azacitidine (AZA) + venetoclax (VEN) with pembrolizumab during the first 6 cycles and compare to control arm.

SECONDARY OBJECTIVES:

1. Assess the investigator-assessed rates of CR/CRi/partial remission (PR)/morphological leukemia free state (MLFS) as defined per the modified International Working Group (IWG) 2003 response criteria with AZA + VEN with pembrolizumab, as well as rates of MRD negative MLFS.

II. Rates of complete remission with partial count recovery (CRh) and hematologic improvement (HI) to red blood cells and platelets.

III. Assess time to MRD negativity and duration of MRD negative state, event free survival (EFS), relapse free survival (RFS), calculated as the time from initial treatment to either disease relapse or death, duration of response (DOR, defined as the time from first CR/CRi to the date of the first documented relapse or death, whichever occurs first) and overall survival (OS).

IV. Assess the proportion of patients who develop severe toxicity.

EXPLORATORY OBJECTIVES:

1. MRD assessment by duplex sequencing (DS) and comparing DS and multiparameter flow cytometry for MRD detection as an exploratory biomarker.

II. Assessment of immune-checkpoint expression and dynamic change of immune cell subsets in response to the combination of checkpoint-inhibition and backbone combination in acute myeloid leukemia (AML).

III. High-throughput sequencing of the T-cell receptor (TCR) Vb CDR3 regions on flow cytometrically sorted t-cell subsets to assess the effect of immunotherapy on the diversity of the t-cell repertoire and assess for correlation to clinical outcomes.

IV. Investigation of protein signatures and ribonucleic acid (RNA) signatures associated with response and efficacy using O-link cytokine panel and RNA-sequencing (seq), respectively.

1. Determination of mutational load by whole exome sequencing to assess for correlation with clinical outcomes, immune infiltrating profile, and T cell repertoire diversity and clonality.

VI. Profiling of deoxyribonucleic acid (DNA) methylation patterns before and after treatment to assess for correlation to response to treatment.

VII. Correlate gut microbiome at baseline and changes in the microbiome with clinical response, both in standard chemotherapy and immunotherapy/chemotherapy therapy settings.

VIII. MRD assessment using duplex sequencing strategy for circulating cell-free tumor DNA and correlation with long-term outcomes.

IX. Exploring different thresholds of MRD negativity using flow cytometry aside from the 0.1% level that will be used for the primary endpoint purposes (e.g. 0.01%).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I (AZA + VEN):

INDUCTION THERAPY PHASE: Patients receive azacitidine intravenously (IV) over 10-40 minutes or subcutaneously (SC) on days 1-7 or days 1-5 in week 1 and 1-2 in week 2. Patients also receive venetoclax orally (PO) on days 1-28 of cycle 1 and days 1-21 or 1-28 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY PHASE: Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7 or days 1-5 in week 1 and 1-2 in week 2. Patients also receive venetoclax PO on days 1-21 or 1-28 (depending on count recovery) for all cycles. Cycles repeat every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity. After completion of 24 cycles, patients who respond to treatment or have stable disease (SD) may continue treatment per physician discretion.

ARM II (AZA + VEN + PEMBROLIZUMAB):

INDUCTION THERAPY PHASE: Patients receive pembrolizumab IV over 30 minutes on day 8 of cycle 1 and every 3 weeks in cycle 2-6, azacitidine IV over 10-40 minutes or SC on days 1-7 or days 1-5 in week 1 and 1-2 in week 2, and venetoclax PO on days 1-28 of cycle 1 and days 1-21 or 1-28 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY PHASE: Patients receive pembrolizumab IV over 30 minutes every 3 weeks, azacitidine IV over 10-40 minutes or SC on days 1-7 or days 1-5 in week 1 and 1-2 in week 2, and venetoclax PO on days 1-21 or 1-28 (depending on count recovery) for all cycles. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. After completion of 24 cycles, patients who respond to treatment or have SD may continue treatment with azacitidine and venetoclax per physician discretion.

Patients in both arms also undergo echocardiography (ECHO) or multigated acquisition (MUGA) scan during screening and bone marrow biopsy and/or aspiration and collection of blood samples throughout the trial, as well as a skin biopsy at baseline.

Patients are followed up every 6 months for up to 3 years.