A Phase I/II Safety and Clinical Activity Study of Combination Azacitidine and Avelumab in Patients With Acute Myeloid Leukemia (AML) and Minimal Residual Disease (MRD)
Overview
- Phase
- Phase 1
- Intervention
- Azacitidine
- Conditions
- Acute Myeloid Leukemia (AML)
- Sponsor
- Memorial Sloan Kettering Cancer Center
- Locations
- 1
- Primary Endpoint
- sustained MRD negativity (Phase II)
- Status
- Withdrawn
- Last Updated
- 7 years ago
Overview
Brief Summary
This is a phase I / II study. The purposes of this study are to: 1) find out what effects, good and/or bad, the combination of the experimental drug avelumab and the drug azacitidine has on people with AML and MRD, and 2) test if the two drugs, avelumab and azacitidine, are effective in getting rid of AML MRD when the drugs are given together in combination.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subjects must be ≥18 years of age.
- •Subjects must have a history of AML as defined by WHO criteria. AML patients with any cytogenetic abnormalities are eligible except for patients with t (15;17) (acute promyelocytic leukemia). AML patients who have never undergone allogeneic stem cell transplant must have adverse-risk AML by ELN criteria77 to be eligible. Patients with a history of therapy related AML, myeloid sarcoma, or patients whose AML evolved from an antecedent MDS or MPN are also eligible. Patients with any molecular mutations are eligible.
- •Subjects must have received therapy for AML and have a bone marrow biopsy within 28 days prior to registration that demonstrates a morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) as defined by European Leukemia Net (ELN) criteria. Patients with prior myeloid sarcoma must have no residual evidence of extramedullary leukemia.
- •Subjects may have received any prior therapy for AML including cytotoxic agents, hypomethylating agents, or other therapeutics to achieve morphologic CR or CRi.
- •Subjects must have MRD in a bone marrow aspirate within 28 days prior to registration from the same bone marrow sample which demonstrates morphologic CR. MRD is identified by multiparameter flow cytometry as a cell population showing deviation from normal antigen-expression patterns seen in specific cell lineages at specific stages of maturation. Any level of residual flow cytometric disease is considered MRD positive.
- •Subjects must be amenable to serial bone marrow biopsies, peripheral blood sampling, and urine sampling during the study.
- •Subjects or their legal representatives must be able to understand and sign an informed consent.
- •Subjects must have ECOG PS of 0 to
- •Subjects must have adequate hematological function defined by absolute neutrophil count (ANC) ≥ 1.0 × 10\^9/L, platelet count ≥ 50 × 10\^9/L, and hemoglobin ≥ 9 g/dL (may have been transfused)
- •Subjects must have adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and AST and ALT levels ≤ 2.5 × ULN
Exclusion Criteria
- •Patients with prior allogeneic stem cell transplantation (SCT) who have had:
- •allo-SCT performed \<3 months prior to enrollment; or
- •immunosuppressive treatment for acute or chronic graft-versus-host disease (GVHD) within 3 months prior to enrollment (with the exception of those patients who required ≤15 mg/day oral prednisone or equivalent); or
- •acute Grade 3 or Grade 4 GVHD at any time in the past (as defined by the modified Seattle Glucksberg Criteria); or
- •prior chronic GVHD (as defined by the NIH Consensus Development Project), persisting for \>6 months, which required systemic immunosuppression (with the exception of those patients who required ≤15 mg/day oral prednisone or equivalent); or
- •a donor lymphocyte infusion (DLI) within 6 months prior to enrollment; or
- •is currently on treatment with GVHD prophylaxis medications tacrolimus, sirolimus, or cyclosporine
- •Subjects with clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid is only required if there is a clinical suspicion of CNS involvement by leukemia during screening.
- •Significant acute or chronic infections including, among others:
- •Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
Arms & Interventions
Azacitidine and Avelumab
All enrolled patients will receive 1 cycle of AZA followed by cycles of combination AZA+Avelumab.
Intervention: Azacitidine
Azacitidine and Avelumab
All enrolled patients will receive 1 cycle of AZA followed by cycles of combination AZA+Avelumab.
Intervention: Avelumab
Outcomes
Primary Outcomes
sustained MRD negativity (Phase II)
Time Frame: 1 year
This is defined as the time from the first dose of azacitidine to a patient"s confirmed MRD negativity on the second bone marrow.
Number of patients with dose limiting toxicities as assessed by CTCAE v4.0
Time Frame: 1 year
Up to 6 pre-allo SCT patients who are evaluable for DLT will be enrolled, with the first 3 patients enrolled in a sequential manner with a 1-week interval between the start of dosing for each patient. If the regimen appears tolerable in the first 3 patients (i.e., ≤ 1 of the first 3 patients enrolled experiences a DLT), then the next 3 patients will be enrolled concurrently. If more than 1 out of 6 in the pre-alloSCT group has a DLT, the trial will stop accrual. The combination will be considered safe in pre-allo SCT patients if one or no patient has a DLT out of the six patients. If the combination is safe in pre-alloSCT patients, additional pre-alloSCT patients will begin enrollment for the expanded phase II portion of the study, and accrual of 6 post-alloSCT patients for separate safety evaluation will begin. Toxicity will be graded on a scale of 1 to 5 as described by the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.