Trial in Progress: A Phase I/II Study to Assess Safety, Tolerability and Preliminary Efficacy of Bexmarilimab in Combination with Standard of Care in Patients with Hematological Malignancies (BEXMAB)

Abstract

Background: Emerging data on the role of leukemic cells on shaping the tumor immune environment places macrophages as target cells and immune checkpoints in acute myeloid leukemia (AML) (Miari et. al. Front. Cell Dev. Biol.2021; Sallman et. al. Blood 2019). CLEVER-1 (common lymphatic endothelial and vascular endothelial receptor-1) constitutes such macrophage checkpoint. The receptor contributes to tumor immune tolerance by antigen clearing and T cell inhibition. In multiple models, tumor growth is significantly reduced in CLEVER-1 absence (Viitala et. al. Clin Cancer Res 2019). CLEVER-1 expression level is a prognostic factor for poor outcomes in AML (Pölönen et. al. Cancer Research 2019) and its suppression inhibits leukemia cell growth. Analyses suggests lower expression is associated with venetoclax sensitivity (Lin et al. Mol Ther 2019). Bexmarilimab (FP-1305; BEX), an IgG4 monoclonal antibody, binds CLEVER-1 and alters the function of macrophages and inactive T cells. BEX was shown to increase antigen presentation, induce proinflammatory cytokines and infiltration of activated T cells (Viitala et. al. Clin Cancer Res 2019). The therapeutic potential of BEX is supported with data from the MATINS study (NCT03733990) evaluating single agent in advanced solid tumors. Up to 40% of patients in selected indications experience disease control (stable disease/partial response) associated with a 65% chance of 1-year overall survival (OS) compared to 11% of patients without disease control. BEX treatment is well tolerated without any dose limiting toxicity (DLT) reported. CLEVER-1 is highly expression on malignant blasts and monocytes of bone marrow from AML and myelodysplastic syndrome (MDS) patients. Treatment of these BM cells with BEX alone or in combination with azacitidine or venetoclax results in enhanced antigen presentation capacity and increased activation markers on effector T cells with synergistic effects (EHA 2022 P380). Study Design and Methods: The PhI/II study investigates BEX treatment plus standard of care in MDS, chronic myelomonocytic leukemia (CMML) frontline or hypomethylating agent (HMA)-failed patients or newly diagnosed AML or relapsed/refractory (r/r) AML patients (NCT05428969). Enrollment is ongoing. Ph I is a dose escalation using a Bayesian optimal interval (BOIN) design to explore 4 dose levels of BEX in a cohort size of 5 with 1.0 mg/kg as starting dose. BEX plus azacitidine (doublet) is assessed in a mixed cohort of MDS, CMML frontline and hypomethylating agent (HMA)-failure patients or r/r AML patients. Dose determination may then be performed in separate indications. BEX plus azacitidine + venetocolax (triplet) will follow a similar BOIN design for dose determination in patients with newly diagnosed AML unfit for induction chemotherapy. BEX is dosed in 28-day cycles Q1W during cycles 1-3 followed by Q2W dosing, until disease progression or intolerable toxicity. Standard of care therapy is administered as per label. During Ph II, selected indications are explored for efficacy when BEX is administered at recommended phase 2 dose (RP2D) determined in the doublet and triplet. Dose expansion follows a 2-Stage design with indication-specific target efficacy rates, including complete remission +/- incomplete hematologic recovery, overall response rate or minimal residual disease (MRD)-negativity. Primary endpoints are safety and tolerability, RP2D of BEX and preliminary efficacy. Secondary endpoints include extended efficacy for duration of response, event free survival and OS. Exploratory endpoints are focused on pharmacodynamic parameters for immunological and cellular read-outs and the association of predictive biomarker of BEX clinical activity in different patient sub-groups. Key eligibility includes patient ≥ 18 years of age presenting with morphologically confirmed diagnosis of either MDS (intermediate-very high rIPSS risk), CMML-2 with indication for azacitidine treatment; CMML and MDS patients with failure to HMA therapy, confirmed diagnosis of r/r AML following at least 1 prior treatment line or diagnosis of AML in patients unfit for induction therapy with indication for azacitidine + venetoclax. Patients with APL or myeloproliferative CMML, active auto-immune disorder or requiring systemic corticosteroid or other immunosuppressive treatment are excluded. Approximately 181 patients at 10 US and EU sites will be enrolled.