Phase 1b Trial of Anti-Immunoglobulin-like Transcript 3 Monoclonal Antibody MK-0482 Monotherapy in Relapsed/Refractory Acute Myeloid Leukemia and Chronic Myelomonocytic Leukemia

Background: Immunoglobulin-like transcript 3 (ILT3) is a cell surface inhibitory receptor expressed on various immune cells including dendritic cells, monocytic myeloid cells, and macrophages. The expression of ILT3 on dendritic cells and myeloid cells is thought to be involved in immune suppression and antigen-specific immune tolerance, contributing to an immunosuppressive tumor microenvironment. Acute myeloid leukemia (AML) is a type of cancer characterized by bone marrow that makes a large number of abnormal blood cells. In monocytic AML, ILT3 is highly expressed, and its signaling can mediate T-cell suppression and promote tumor infiltration (Deng M et al. Nature. 2018;562:605-609). Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by dysplasia, abnormal production and accumulation of monocytic cells, and with an elevated risk of transforming into AML. Based on the M2GEN database, ILT3 is also highly expressed in CMML. Thus, targeting ILT3 may exhibit antitumor activity in patients with AML and CMML. Currently, limited effective treatments are available for AML and CMML, especially in the relapse and refractory setting. MK-0482, a humanized IgG4 anti-ILT3 monoclonal antibody, has been evaluated as monotherapy and in combination with pembrolizumab at doses ≤2250 mg every 3 weeks (Q3W) in patients with advanced solid tumors. Patients treated with MK-0482 had a manageable safety profile, and modest antitumor activity was observed with MK-0482 plus pembrolizumab (Gutierrez M et al. J Clin Oncol. 2022;40. Abstract 2505). In this phase 1b study (NCT05038800), we are evaluating the safety and the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of MK-0482 in relapsed or refractory (r/r) AML and CMML. Study Design and Methods: Adult patients with AML with myelomonocytic or monoblastic/monocytic differentiation or CMML and with confirmed refractory or relapsed disease after treatment with available therapies will be eligible for enrollment. All patients must have an ECOG performance status of 0-2, adequate organ function, and a white blood cell count ≤20 × 109/L. Patients with active central nervous system leukemia, isolated extramedullary disease (ie no leukemic involvement), acute promyelocytic leukemia, or who have previously received allogeneic stem cell or organ transplant <60 days of treatment will be excluded. In part 1 (dose escalation), MK-0482 will be evaluated at dose levels ranging from 7.5 mg to 750 mg Q3W for ≤35 cycles with an accelerated titration design followed by a modified toxicity probability interval design in ~20 patients. After the recommended phase 2 dose (RP2D) is determined, 10 to 15 additional patients with AML with myelomonocytic or monoblastic/monocytic differentiation will be enrolled in part 2 (dose expansion). The primary objective of the study is to determine safety and tolerability and RP2D. Secondary objectives include characterizing the PK profile of MK-0482 monotherapy and antileukemia activities in AML as assessed by complete remission (CR), composite CR, and objective response per the 2017 European Leukemia Net AML response criteria. Exploratory objectives include assessment of receptor occupancy in peripheral blood and tumor biopsies, molecular biomarkers, and antileukemic activities in patients with CMML. Dose-limiting toxicities will be observed for 21 days after the first dose in cycle 1 and adverse events (AEs) will be assessed through 30 days after treatment discontinuation (90 days for serious AEs; 30 days if new anticancer therapy is initiated) per National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Disease assessment will be performed by investigator at baseline and prior to day 1 of cycles 3, 5, and 7, followed by every 3 cycles until disease progression or confirmed CR. Samples for PK analyses will be collected before and after treatment on day 1 of cycles 1-4, 6, 8, and every 4 cycles thereafter. The study is currently ongoing.