Relatlimab With Nivolumab and 5-Azacytidine for the Treatment of AML

An Open-Label Phase II Study of Relatlimab (BMS-986016) With Nivolumab (BMS-936558) in Combination With 5-Azacytidine for the Treatment of Patients With Refractory/Relapsed Acute Myeloid Leukemia and Newly Diagnosed Older Acute Myeloid Leukemia Patients

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).

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