An Open-Label Phase I/II Study of Relatlimab (BMS-986016) with Nivolumab (BMS-936558) in Combination with 5-Azacytidine for Relapsed/Refractory Acute Myeloid Leukemia and in Combination with 5-Azacytidine and Venetoclax for Newly Diagnosed, Previously Untreated Patients with Acute Myeloid Leukemia Negative for NPM1 and IDH 1/2 Mutations Who Are Ineligible for Intensive Chemotherapy (AARON)

Prior treatment

• Confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent.
• Allogeneic hematopoietic stem cell transplantation within the last 100 days before first study drug administration.
• History of life-threatening toxicity related to prior immune therapy.
• Previous treatment with immunotherapeutic drugs targeting PD-1/PD-L1 in combination with 5-azacytidine.
• Previous treatment with LAG-3 targeted agents.

Other illness

• Active uncontrolled pneumonitis.
• Active uncontrolled infection.
• Uncontrolled or significant cardiovascular disease.
• Known positivity for hepatitis B by surface antigen expression or active hepatitis C infection.
• Other medical, psychological, or social condition that may interfere with study participation or compliance, or compromise patient safety.
• Known allergy or hypersensitivity to 5-azacytidine, nivolumab, relatlimab, or any of their components.
• Known allergy or hypersensitivity to venetoclax, or any of its components, for patients in Cohort 2.
• Known history of severe interstitial lung disease or severe pneumonitis.
• Known history (active, known, or suspected) of any of the following autoimmune diseases: – inflammatory bowel disease – rheumatoid arthritis – systemic progressive sclerosis – systemic lupus erythematosus – autoimmune vasculitis.

Lab values

• Troponin T (TnT) or I (TnI) > 2 × institutional ULN.

Other

• Acute promyelocytic leukemia (APL).
• Symptomatic or poorly controlled CNS leukemia.
• Organ allografts.
• Active GvHD > grade A.
• Known human immunodeficiency virus seropositivity.
• Biphenotypic or bilineage leukemia.
• Patients unwilling or unable to comply with the protocol.
• Patients who are pregnant or breastfeeding.
• Prisoners and subjects who are compulsory detained.

• Cohort 1 (R/R AML): Patients with AML who have failed first line induction chemotherapy (consisting of a minimum of two intensive chemotherapy cycles, e.g. 7+3 or HAM) or patients with AML who have relapsed after achieving CR, CRi, or CRp, or patients who have failed up to one prior salvage therapy.
• At least 2 weeks OR at least 5 half-lives interval from prior treatment to time of initiation of study medication.
• Written informed consent.
• GvHD of grade ≤A on ≤10 mg prednisone without any additional immunosuppressive therapies (tacrolimus, ciclosporin, etc.).
• Negative pregnancy test and adequate methods of contraception for females of childbearing potential, adequate methods of contraception for males.
• Cohort 2 (frontline non-fit AML): Patients with previously untreated AML, negative for mutations in NPM1 and IDH 1/2 genes, who are ineligible for or decline standard induction therapy.
• Patients not eligible for intensive induction chemotherapy and/or allogeneic stem cell transplant.
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2.
• Age ≥18 years.
• Total bilirubin ≤2 x upper limit of normal (ULN, ≤3 × ULN if due to leukemic involvement or Gilbert’s syndrome).
• AST and ALT ≤2.5 × ULN (≤5.0 × ULN if due to leukemic involvement).
• Serum creatinine ≤2 × ULN or glomerular filtration rate (GFR) ≥50 mL/h.
• Adequate cardiac function: TTE with documented LVEF ≥50%.