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

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).

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Azacitidine Injection; Drug: Nivolumab; Drug: Relatlimab

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Marion Subklewe, MD; Phone Number: +498944000; Email: marion.subklewe@med.uni-muenchen.de
• Study Contact Backup: Name: Veit Bücklein, MD; Phone Number: +498944000; Email: veit.buecklein@med.uni-muenchen.de

Study Locations

• Germany
  • Munich, Germany, 81377
    • Recruiting
    • University Hospital, LMU Munich
    • Contact: Marion Subklewe, MD; Phone Number: +49-894400-0; Email: marion.subklewe@med.uni-muenchen.de
    • Contact: Veit Bücklein, MD; Phone Number: +49-89-4400-0; Email: veit.buecklein@med.uni-muenchen.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunological changes	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	During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct
Molecular changes	To study the methylation status of blast DNA in the peripheral blood and bone marrow in response to relatlimab + nivolumab + 5-azacytidine therapy	During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct

Collaborators and Investigators

• Sponsor: Ludwig-Maximilians - University of Munich
• Investigators: Principal Investigator: Marion Subklewe, MD, Department of Medicine III, University of Munich

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 5, 2021
• Primary Completion (ANTICIPATED): March 1, 2025
• Study Completion (ANTICIPATED): March 1, 2026

Study Registration Dates

• First Submitted: May 14, 2021
• First Submitted That Met QC Criteria: May 30, 2021
• First Posted (ACTUAL): June 4, 2021

Study Record Updates

• Last Update Posted (ACTUAL): November 8, 2022
• Last Update Submitted That Met QC Criteria: November 3, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: AML; relapsed; refractory; checkpoint blockade; immune checkpoint inhibition
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Azacitidine
• Other Study ID Numbers: CA224-065

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes