AARON: Relatlimab With Nivolumab and 5-Azacytidine for the Treatment of AML
Study Details
Study Description
Brief Summary
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:
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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
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objective response rate (ORR) of the combination therapy in the phase II part of the study (up to 24 patients).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Combination therapy 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
s.c. 75 mg/m2 BSA for 7 days
Drug: Nivolumab
480 mg i.v.
Drug: Relatlimab
80-160mg i.v.
|
Outcome Measures
Primary Outcome Measures
- Maximum tolerated dose (MTD) [after completion of the first cycle in the fist 6-12 patients, approximately during the first 6-12 months of study conduct]
To determine the MTD of relatlimab in combination with nivolumab and 5-azacytidine in patients with R/R AML.
- Dose-limiting toxicities (DLTs) [after completion of the first cycle in the fist 6-12 patients, approximately during the first 6-12 months of study conduct]
To determine the DLT of relatlimab in combination with nivolumab and 5-azacytidine in patients with R/R AML.
- Objective response rate (ORR) [During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct]
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
Secondary Outcome Measures
- Hematologic improvement [During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct]
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 achieve a hematologic improvement (HI) in platelets, hemoglobin, or absolute neutrophil count (ANC)
- Blast reduction [During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct]
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 achieve a blast reduction (defined as ≥50% reduction in blast percentage compared to baseline blast percentage in bone marrow)
- Duration of response (DOR) [During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct]
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.
- Disease-free survival (DFS) [During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct]
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.
- Overall survival (OS) [During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct]
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.
Other Outcome Measures
- Immunological changes [During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct]
To study immunological changes in the peripheral blood and bone marrow in response to relatlimab + nivolumab + 5-azacytidine therapy, assessed by the frequency of T-cell (subsets), regulatory T cells, and immune checkpoint expression on blasts and T cells by flow cytometry and RNA Sequencing
- Molecular changes [During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct]
To study the methylation status of blast DNA in the peripheral blood and bone marrow in response to relatlimab + nivolumab + 5-azacytidine therapy
Eligibility Criteria
Criteria
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:
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Patients not eligible for intensive induction chemotherapy and/or allogeneic stem cell transplant.
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Age ≥18 years
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ECOG Performance Status ≤2
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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
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Adequate cardiac function: TTE with documented LVEF ≥50%
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At least 2 weeks OR at least 5 half-lives interval from prior treatment to time of initiation of study medication
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GvHD of grade ≤A on ≤10 mg prednisone without any additional immunosuppressive therapies (tacrolimus, ciclosporin, etc.)
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Written informed consent
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Negative pregnancy test and adequate methods of contraception for females of childbearing potential, adequate methods of contraception for males
Exclusion Criteria:
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Acute promyelocytic leukemia (APL)
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Biphenotypic or bilineage leukemia
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Known allergy or hypersensitivity to 5-azacytidine, nivolumab, relatlimab, or any of their components
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History of life-threatening toxicity related to prior immune therapy
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Previous treatment with immunotherapeutic drugs targeting PD-1/PD-L1 in combination with 5-azacytidine
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Previous treatment with LAG-3 targeted agents
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Known history of severe interstitial lung disease or severe pneumonitis
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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
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Active uncontrolled pneumonitis
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Active uncontrolled infection
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Symptomatic or poorly controlled CNS leukemia
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Confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
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Uncontrolled or significant cardiovascular disease
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Troponin T (TnT) or I (TnI) > 2 × institutional ULN
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Organ allografts
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Allogeneic hematopoietic stem cell transplantation within the last 100 days before first study drug administration
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Active GvHD > grade A
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Known human immunodeficiency virus seropositivity
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Known positivity for hepatitis B by surface antigen expression or active hepatitis C infection
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Other medical, psychological, or social condition that may interfere with study participation or compliance, or compromise patient safety
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Patients unwilling or unable to comply with the protocol
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Patients who are pregnant or breastfeeding
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Prisoners and subjects who are compulsory detained
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University Hospital, LMU Munich | Munich | Germany | 81377 |
Sponsors and Collaborators
- Ludwig-Maximilians - University of Munich
Investigators
- Principal Investigator: Marion Subklewe, MD, Department of Medicine III, University of Munich
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CA224-065