OX40, Venetoclax, Avelumab, Glasdegib, Gemtuzumab Ozogamicin, and Azacitidine in Relapsed or Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVES: I. To evaluate the safety of multiple combination regimens of IO-agents (PF04518600 \[Ox40 agonist monoclonal antibody (mAb)\], avelumab \[PD-L1 antagonist mAb\], hypomethylator therapy (azacitidine), anti CD33 mAb (gemtuzumab ozogamycin, GO), Bcl-2 inhibitor (venetoclax) and smoothened pathway inhibitor (glasdegib) in patients with relapsed/refractory (RR) acute myeloid leukemia (AML). II. To evaluate the composite complete response (CRc) defined as complete response (CR) + complete response with incomplete recovery of platelets (CRp) + complete response with incomplete recovery of counts (CRi) within 3 months of therapy initiation in patients with RR AML of: Arm A. PF-04518600 alone, Arm B. azacitidine + venetoclax + GO, Arm C. azacitidine + aveluma + GO, Arm D. azacitidine + venetoclax + avelumab, Arm E. Azacitidine + avelumab + PF-04518600, Arm F. GO + glasdegib. SECONDARY OBJECTIVES: I. To assess the morphologic leukemia free survival (MLFS), partial response (PR), hematologic improvement (HI) rate of patients with RR AML treated on arms A-F. II. To assess relapse-free survival (RFS), time to next therapy (TNT), 4-week and 8-week mortality, and overall survival (OS) of patients with RR AML treated on arms A-F. III. To assess minimal residual disease (MRD) by multiparametric flow-cytometry at response (+/- 1 month) and assess correlation of MRD to OS in arms A-F. EXPLORATORY OBJECTIVES: I. To study immunological and molecular features at baseline and at predefined time-points on-therapy with each combination in the peripheral blood and bone marrow to include quantification of immune ligand expression by the AML/myelodysplastic syndrome (MDS) blasts and AML/MDS stromal components (myeloid-derived suppressor cell \[MDSC\]s, monocytes and mesenchymal stem cell \[MSC\]s) including galectin 9, 4-1BBL, ICOSL, PD-L1, PD-L2, OX-40L, CD137L, others. II. To study immunological and molecular features at baseline and at predefined time-points on-therapy with each combination in the peripheral blood and bone marrow to include determination of the quantitative expression of positive and negative co-stimulatory molecules including 4-1BB, CTLA-4, ICOS, PD-1, OX40, LAG-3, TIM-3, HLA-DR, Ki67, others on T-lymphocyte subsets. III. To study immunological and molecular features at baseline and at predefined time-points on-therapy with each combination in the peripheral blood and bone marrow to include identification of the immunophenotype of tumor-infiltrating T-lymphocytes (TILs) pre- and post-therapy including CD8+, CD4+ effector, CD4+ regulatory TILs and central memory, effector memory, and naive T-cell subsets among the CD4 and CD8 populations. IV. To develop a micro-array based gene expression profile (GEP) predictor of response to the immune combinations using either baseline ribonucleic acid (RNA) sequencing and/or nanostring. V. To perform a validated next generation sequencing (NGS)-based analysis for the detection of somatic mutations in the coding sequences of 28 genes commonly mutated in AML at baseline and on treatment to identify baseline predictors and clonal evolution on treatment and/or whole exome sequencing (WES) in selected cases. VI. To identify clonal T-cells by performing T-cell repertoire analysis at baseline and longitudinally on therapy on the peripheral blood and/o bone marrow samples. VII. To assess levels of cytokines at baseline and longitudinally on therapy in peripheral blood and/or bone marrow. OUTLINE: This is a phase I, dose escalation study of anti-OX40 antibody PF-04518600 followed by a phase II study. Patients are assigned to 1 of 6 arms. ARM A: Patients receive anti-OX40 antibody PF-04518600 intravenously (IV) over 60 minutes on days 1 and 14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive azacitidine IV over 10-40 minutes or via injection subcutaneously (SC) on days 1-7 or 1-5 and 8-9. Patients also receive venetoclax orally (PO) on days 1-28 and GO IV over 2 hours on day 8. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM C: Patients receive azacitidine and GO as in Arm B. Patients also receive avelumab IV over 60 minutes on days 1 and 14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM D: Patients receive azacitidine and venetoclax as in Arm A and avelumab as in Arm C. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM E: Patientss receive azacitidine and avelumab as in Arm C and anti-OX40 antibody PF-04518600 as in Arm A. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM F: Patients receive GO IV over 2 hours on days 1, 4, and 7, and glasdegib PO on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After conclusion of study treatment, patients are followed up at 30 days, then every 3-6 months for up to 5 years.