Overview

The clinical trial will test the safety and tolerability of a combination therapy (azacitidine in combination with two checkpoint inhibitors, nivolumab [Anti-PD1] and relatlimab [Anti-LAG3]) in patients with relapsed/refractory Acute Myeloid Leukemia (AML) and patients ≥ 65 years with initial diagnosis of AML.

Primary objectives are:

• maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the combination therapy during the lead-in phase of the clinical trial (6-12 patients) and
• objective response rate (ORR) of the combination therapy in the phase II part of the study (up to 24 patients).

Eligibility

Inclusion Criteria:

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 complete remission (CR), CRi, or CRp, or patients who have failed up to one prior salvage therapy

Cohort 2 (frontline older AML):

• Patients aged ≥65 years with previously untreated AML who are unfit for or decline standard induction therapy.

General inclusion criteria:

• Patients not eligible for intensive induction chemotherapy and/or allogeneic stem cell transplant.
• Age ≥18 years
• ECOG Performance Status ≤2
• Adequate organ function:

        Total bilirubin ≤2 x 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%
          -  At least 2 weeks OR at least 5 half-lives interval from prior treatment to time of
             initiation of study medication
          -  GvHD of grade ≤A on ≤10 mg prednisone without any additional immunosuppressive
             therapies (tacrolimus, ciclosporin, etc.)
          -  Written informed consent
          -  Negative pregnancy test and adequate methods of contraception for females of
             childbearing potential, adequate methods of contraception for males
        Exclusion Criteria:
          -  Acute promyelocytic leukemia (APL)
          -  Biphenotypic or bilineage leukemia
          -  Known allergy or hypersensitivity to 5-azacytidine, nivolumab, relatlimab, or any of
             their components
          -  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
          -  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
          -  Active uncontrolled pneumonitis
          -  Active uncontrolled infection
          -  Symptomatic or poorly controlled CNS leukemia
          -  Confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year
             prior to informed consent
          -  Uncontrolled or significant cardiovascular disease
          -  Troponin T (TnT) or I (TnI) > 2 × institutional ULN
          -  Organ allografts
          -  Allogeneic hematopoietic stem cell transplantation within the last 100 days before
             first study drug administration
          -  Active GvHD > grade A
          -  Known human immunodeficiency virus seropositivity
          -  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
          -  Patients unwilling or unable to comply with the protocol
          -  Patients who are pregnant or breastfeeding
          -  Prisoners and subjects who are compulsory detained