Trial in Progress: An Open-Label Phase II Study of Relatlimab with Nivolumab in Combination with 5-Azacytidine for the Treatment of Patients with Relapsed/Refractory and Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia (AARON)

The approval of venetoclax in combination with hypomethylating agents (HMA) for newly diagnosed acute myeloid leukemia (AML) has significantly improved the outcomes of patients that are not fit for intensive chemotherapy regimens. However, a considerable proportion of patients are primary refractory or relapse, highlighting the need for novel combinatorial treatment options in this patient population.

Preclinical models have shown that blocking of the PD-1/PD-L1 pathway enhances antileukemic responses. However, in AML, early clinical trials evaluating the single-agent efficacy of nivolumab and other PD-1 inhibitors have demonstrated only limited activity. Based on preclinical findings that hypomethylating agents (HMA) like 5-Azacytidin (AZA) can induce an upregulation of PD-1 expression and the IFNγ signaling pathway, combinatorial treatment approaches have been studied. In relapsed/refractory (R/R) AML, the combination of AZA + Nivolumab demonstrated higher response rates and improved median overall survival compared to historical outcomes with HMA-based salvage clinical trials (Daver N et al, Cancer Discovery 2019). In our own previous work, we uncovered that blocking the inhibitory checkpoint molecule LAG-3 significantly increases the generation of anti-leukemic T-cell responses, in particular in combination with PD-1/PD-L1 blocking (Lichtenegger FS et al, Front Immunol 2018). Clinical trials are evaluating relatlimab, a monoclonal IgG4 antibody blocking LAG-3 and its interaction with HLA-class II molecules, in various indications, and it has recently been approved in combination with nivolumab for the treatment of patients with untreated advanced malignant melanoma by the FDA.

Here, we describe a trial designed to assess the safety and efficacy of the combination of 5-azacytidine, nivolumab, and relatlimab in patients with r/r AML (cohort 1). The AARON trial (NCT04913922) is a phase 2, single arm, open-label trial. Additionally, we plan to amend the protocol to enroll patients aged ≥65 years with previously untreated AML (excluding patients with NPM1 and IDH1/2 mutations) who are unfit for or decline standard induction therapy (cohort 2). For this cohort, the trial will evaluate the combination of relatlimab, nivolumab and 5-azacytidine in combination with venetoclax. Importantly, in preclinical data venetoclax has been shown to promote T cell-mediated antileukemic activity (Lee JB et al, Blood 2021), making it a promising combination partner. The study will enroll a total of 30 adult patients with histologically or cytologically documented AML (excluding APL, and excluding patients with NPM1 and IDH1/2 mutations in the first-line cohort). A lead-in phase, recruited independently for both patient cohorts, will establish the safety of the study treatment in 6-12 patients per cohort. Patients must have adequate organ function and an ECOG performance score of ≤2. Patients with previous allogeneic stem cell transplantation can be enrolled in cohort 1 (from day +100 after allo-SCT) in the absence of higher-grade GvHD. Pre-treatment with HMAs is allowed for patients in cohort 1. Patients with a history of or active autoimmune disease are excluded.

5-azacytidine is applied as in routine care (75 mg/m² BSA, days 1-7 of a 4-week cycle). Nivolumab (480mg flat dose) and relatlimab (160mg flat dose) are infused on day 1 of each cycle. For cohort 2, we plan to dose venetoclax at 70mg daily (with mandatory posaconazole co-medication from d1 to 28, or shorter in case of significant hematotoxicity). If dose-limiting toxicities occur in ≥2/6 patients in the lead-in phase, the dose of relatlimab will be reduced to 80mg (flat dose), and the safety of the treatment will be re-assessed with a new 6-patient lead-in phase. Response will be assessed after completion of cycle 1, then every 1-3 cycles.

The primary endpoint of the lead-in phase is the establishment of a recommended phase 2 dose, and overall response rate. The latter will be assessed in both patients from the lead-in and the expansion phase. Secondary endpoints, assessed in all enrolled patients, include the safety, duration of response and survival. A comprehensive accompanying immunomonitoring program will study immunological changes in the peripheral blood and bone marrow.

Funding: Bristol-Myers Squibb.

Buecklein:Miltenyi Biotech: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Amgen: Honoraria; Gilead: Honoraria. Schmidt:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Kite Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Bayer Healthcare: Research Funding; Janssen: Other: Travel Support. Daver:Agios, Celgene, SOBI and STAR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos and Jazz Pharmaceuticals: Other: Data monitoring committee member; Karyopham Therapeutics and Newave Pharmaceutical: Research Funding; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Novartis, Jazz, Amgen, Servier, Karyopharm, Trovagene, Trillium, Syndax, Gilead, Pfizer, Bristol Myers Squibb, Kite, Actinium, Arog, Immunogen, Arcellx, and Shattuck: Consultancy, Other: Advisory Role; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Gilead, Immunogen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi, Fate, Amgen, Kite, Novartis, Astex, KAHR, Shattuck, Sobi, Glycomimetics, Trillium: Research Funding. Subklewe:Bristol-Myers Squibb: Research Funding; Miltenyi Biotech: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Morphosys: Research Funding; Roche: Consultancy, Research Funding; Seagen: Research Funding; Takeda: Other: Travel support; Pfizer: Consultancy; Seattle Genetics: Research Funding.

Nivolumab and relatlimab are not approved for treatment of AML