An Open-Label Phase I/II Study of Relatlimab (BMS-986016) with Nivolumab (BMS-936558) in Combination with 5-Azacytidine for Relapsed/Refractory Acute Myeloid Leukemia and in Combination with 5-Azacytidine and Venetoclax for Newly Diagnosed, Previously Untreated Patients with Acute Myeloid Leukemia Negative for NPM1 and IDH 1/2 Mutations Who Are Ineligible for Intensive Chemotherapy (AARON)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Klinikum der Universitaet Muenchen AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

27 Jan 2021 → 30 Mar 2026

Decision date (initial)

2024-10-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Bristol Myers Squibb GmbH & Co. KGaA

External identifiers

EU CT number

2024-514948-89-00

EudraCT number

2018-002939-21

ClinicalTrials.gov

NCT04913922

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

Lead-in phase I:
• To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of relatlimab in combination with nivolumab and 5-azacytidine in patients with relapsed/refractory (R/R) AML.
• To determine the MTD and DLT of relatlimab in combination with nivolumab, 5-azacytidine and venetoclax in frontline non-fit AML patients

Expansion phase II:
• To estimate the overall response rate (ORR) to treatment with relatlimab + nivolumab + 5-azacytidine in patients with R/R AML.
• To estimate the ORR to treatment with relatlimab + nivolumab + 5-azacytidine + venetoclax in frontline non-fit AML patients

Secondary objectives 6

1. To determine the safety of therapy with relatlimab + nivolumab + 5-azacytidine for patients with R/R AML.
2. To determine the safety of therapy with relatlimab + nivolumab + 5-azacytidine + venetoclax for frontline non-fit AML patients.
3. To determine the number of patients with R/R AML who have a hematologic improvement (HI) in platelets, hemoglobin, or absolute neutrophil count (ANC) and the number of patients with R/R AML who achieve ≥50% reduction in blasts on therapy with relatlimab + nivolumab + 5-azacytidine.
4. To determine the number of frontline non-fit AML patients who have an HI in platelets, hemoglobin, or ANC and the number of frontline non-fit AML patients who have ≥50% reduction in blasts on therapy with relatlimab + nivolumab + 5-azacytidine + venetoclax.
5. To assess the duration of response, disease-free survival (DFS), and overall survival (OS) of patients with R/R AML treated with relatlimab + nivolumab + 5-azacytidine.
6. To assess the duration of response, DFS, and OS in frontline non-fit AML patients treated with relatlimab + nivolumab + 5-azacytidine + venetoclax.

Conditions and MedDRA coding

Acute Myeloid Leukemia

Regulatory references

Scientific advice from competent authorities

Paul-Ehrlich-Institut

Plan to share IPD

Yes

IPD plan description

Data obtained through this study may be provided to qualified researchers with academic interest in the immunotherapy of AML. Access to trial IPD can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal. Data or samples shared will be deidentified. Approval of the request and execution of all applicable agreements (i.e. a material transfer agreement) are prerequisites to the sharing of data with the requesting party. Data requests can be submitted starting 9 months after article publication.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 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 CR, CRi, or CRp, or patients who have failed up to one prior salvage therapy.
2. Cohort 2 (frontline non-fit AML): Patients with previously untreated AML, negative for mutations in NPM1 and IDH 1/2 genes, who are ineligible for or decline standard induction therapy.
3. Patients not eligible for intensive induction chemotherapy and/or allogeneic stem cell transplant.
4. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2.
5. Age ≥18 years.
6. Total bilirubin ≤2 x upper limit of normal (ULN, ≤3 × ULN if due to leukemic involvement or Gilbert’s syndrome).
7. AST and ALT ≤2.5 × ULN (≤5.0 × ULN if due to leukemic involvement).
8. Serum creatinine ≤2 × ULN or glomerular filtration rate (GFR) ≥50 mL/h.
9. Adequate cardiac function: TTE with documented LVEF ≥50%.
10. At least 2 weeks OR at least 5 half-lives interval from prior treatment to time of initiation of study medication.
11. Written informed consent.
12. GvHD of grade ≤A on ≤10 mg prednisone without any additional immunosuppressive therapies (tacrolimus, ciclosporin, etc.).
13. Negative pregnancy test and adequate methods of contraception for females of childbearing potential, adequate methods of contraception for males.

Exclusion criteria 24

1. Acute promyelocytic leukemia (APL).
2. Biphenotypic or bilineage leukemia.
3. Known allergy or hypersensitivity to 5-azacytidine, nivolumab, relatlimab, or any of their components.
4. Known allergy or hypersensitivity to venetoclax, or any of its components, for patients in Cohort 2.
5. History of life-threatening toxicity related to prior immune therapy.
6. Previous treatment with immunotherapeutic drugs targeting PD-1/PD-L1 in combination with 5-azacytidine.
7. Previous treatment with LAG-3 targeted agents.
8. Known history of severe interstitial lung disease or severe pneumonitis.
9. 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.
10. Active uncontrolled pneumonitis.
11. Active uncontrolled infection.
12. Symptomatic or poorly controlled CNS leukemia.
13. Confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent.
14. Uncontrolled or significant cardiovascular disease.
15. Troponin T (TnT) or I (TnI) > 2 × institutional ULN.
16. Organ allografts.
17. Allogeneic hematopoietic stem cell transplantation within the last 100 days before first study drug administration.
18. Active GvHD > grade A.
19. Known human immunodeficiency virus seropositivity.
20. Known positivity for hepatitis B by surface antigen expression or active hepatitis C infection.
21. Other medical, psychological, or social condition that may interfere with study participation or compliance, or compromise patient safety.
22. Patients unwilling or unable to comply with the protocol.
23. Patients who are pregnant or breastfeeding.
24. Prisoners and subjects who are compulsory detained.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Lead-in phase I: MTD and DLT of relatlimab in combination with nivolumab and 5-azacytidine in patients with R/R AML.
2. Lead-in phase I: MTD and DLT of relatlimab in combination with nivolumab and 5-azacytidine and venetoclax in frontline non-fit AML patients.
3. Expansion phase II: ORR to treatment with relatlimab + nivolumab + 5- azacytidine in patients with R/R AML.
4. Expansion phase II: ORR to treatment with relatlimab + nivolumab + 5- azacytidine + venetoclax in frontline non-fit AML patients.

Secondary endpoints 8

1. % of grade I/II and grade III/IV toxicities for patients with R/R AML on therapy with relatlimab + nivolumab + 5- azacytidine.
2. % of grade I/II and grade III/IV toxicities for frontline non-fit AML patients on therapy with relatlimab + nivolumab + 5- azacytidine + venetoclax.
3. Number of patients with R/R AML who achieve a HI in platelets, hemoglobin, or ANC on therapy with relatlimab + nivolumab + 5-azacytidine.
4. Number of patients with R/R AML who achieve ≥50% reduction in blasts on therapy with relatlimab + nivolumab + 5-azacytidine.
5. Number of frontline non-fit AML patients who have an HI in platelets, hemoglobin, or ANC on therapy with relatlimab + nivolumab + 5-azacytidine + venetoclax.
6. Number of frontline non-fit AML patients who have ≥50% reduction in blasts on therapy with relatlimab + nivolumab + 5-azacytidine + venetoclax.
7. Duration of response, Disease-free survival (DFS), and Overall Survival (OS) of patients with R/R AML treated with relatlimab + nivolumab + 5-azacytidine.
8. Duration of response, DFS, and OS in frontline non-fit AML patients treated with relatlimab + nivolumab + 5-azacytidine + venetoclax.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Klinikum der Universitaet Muenchen AöR

Sponsor organisation

Klinikum der Universitaet Muenchen AöR

Address

Marchioninistrasse 15, Hadern Hadern

City

Munich

Postcode

81377

Country

Germany

Scientific contact point

Organisation

Klinikum der Universitaet Muenchen AöR

Contact name

Prof. Dr. Marion Subklewe

Public contact point

Organisation

Klinikum der Universitaet Muenchen AöR

Contact name

Department of Medicine III

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications