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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Azacitidine Injection
* Drug: Nivolumab
* Drug: Relatlimab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination therapy<br>5-azacitidine 75 mg/m2 body surface area s.c. for 7 days nivolumab 480mg i.v. day 1 relatlimab 80-160mg i.v. day 1 repeat day 28 | Drug: Azacitidine Injection<br>* s.c. 75 mg/m2 BSA for 7 days<br>Drug: Nivolumab<br>* 480 mg i.v.<br>Drug: Relatlimab<br>* 80-160mg i.v.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | To determine the MTD of relatlimab in combination with nivolumab and 5-azacytidine in patients with R/R AML. | after completion of the first cycle in the fist 6-12 patients, approximately during the first 6-12 months of study conduct | 
| Dose-limiting toxicities (DLTs) | To determine the DLT of relatlimab in combination with nivolumab and 5-azacytidine in patients with R/R AML. | after completion of the first cycle in the fist 6-12 patients, approximately during the first 6-12 months of study conduct | 
| Objective response rate (ORR) | To estimate the ORR to treatment with relatlimab + nivolumab + 5-azacytidine in patients with R/R AML and Patients ≥65 years with initial diagnosis of AML | During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematologic improvement | To determine the number of patients with R/R AML or Patients ≥65 years with initial diagnosis of AML treated with relatlimab + nivolumab + 5-azacytidine who have a hematologic improvement (HI) in platelets, hemoglobin, or absolute neutrophil count (ANC) | During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct | 
| Blast reduction | To determine the number of patients with R/R AML or Patients ≥65 years with initial diagnosis of AML treated with relatlimab + nivolumab + 5-azacytidine who have a blast reduction (defined as ≥50% reduction in blast percentage compared to baseline blast percentage in bone marrow) | During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct | 
| Duration of response (DOR) | To assess the duration of response (DOR) of patients with R/R AML or Patients ≥65 years with initial diagnosis of AML treated with relatlimab + nivolumab + 5-azacytidine. | During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct | 
| Disease-free survival (DFS) | To assess the disease-free survival (DFS) of patients with R/R AML or Patients ≥65 years with initial diagnosis of AML treated with relatlimab + nivolumab + 5-azacytidine. | During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct | 
| Overall survival (OS) | To assess the overall survival (OS) of patients with R/R AML or Patients ≥65 years with initial diagnosis of AML treated with relatlimab + nivolumab + 5-azacytidine. | During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, relapsed, refractory, checkpoint blockade, immune checkpoint inhibition