A first-in-human study of stx-0712, a CCR2+ cytotoxicity targeting chimera (CyTAC™) in patients with chronic myelomonocytic leukemia (CMML) and Acute Myeloid Leukemia (AML)

Abstract Background and Significance: CMML is a myeloid neoplasm characterized by hematopoietic stem and progenitor cell (HSPCs) monocytic bias, leading to downstream monocyte expansion that plays a key role in disease maintenance and progression. Monocytes in CMML express high surface expression of the homing C-C chemokine receptor 2 (CCR2), which promotes malignant monocyte survival. Expansion of CCR2+ monocytic progenitors drives acute transformation in CMML and contributes to venetoclax resistance in AML. For these reasons, CCR2 is a potential novel therapeutic target in CMML and monocytic AML. The CyTAC platform was designed to enable targeting of cell surface antigens that demonstrate limited or ineffective binding to conventional therapeutic antibodies. A CyTAC is a heterobivalent small molecule that binds to both a target of choice and to a fully humanized monoclonal antibody. STX-0712 comprises a CCR2 CyTAC which potently binds to CCR2 on malignant cells, and a CyTAC humanized ADCC-enabling monoclonal antibody, which when combined eliminates target cells via enhanced effector-mediated killing in the presence of NK cells. We have demonstrated that treatment with STX-0712 ex vivo results in human target engagement and pharmacodynamic activity, and in vivo leads to depletion of CCR2 MO1 monocytes in a potent and dose-dependent manner in CMML and AML (ASH 2024). Therapeutic depletion of CCR2+ malignant monocytes presents a novel opportunity to develop a potential disease-modifying targeted therapeutic agent. We have designed a first-in-human, phase 1 clinical trial to evaluate the effect of CCR2 CyTAC in patients with refractory/resistant CMML, and relapsed/refractory monocytic or monocytic predominant AML. Study Design and Methods This is a phase 1, first-in-human, open-label, multicenter clinical trial based in the USA to evaluate STX-0712 as a monotherapy in patients with CMML and AML who have no remaining treatment options known to confer clinical benefit. STX-0712 will be administered as a single intravenous (IV) infusion every 3 weeks (additional regimen schedules may be explored) until evidence of disease progression, death, intolerance to study medication, or withdrawal of consent. The study consists of a dose-escalation and dose-expansion part and includes two cohorts: Cohort 1 (refractory/resistant CMML) and Cohort 2 (relapsed/refractory monocytic or monocytic predominant AML). Dose escalation will begin in participants with CMML using the Bayesian Optimal Interval (BOIN) design, with a minimum of three patients enrolled at each dose level. Backfilling of up to two cleared dose levels will be initiated once efficacious exposure levels are reached and at least one CMML participant has achieved a complete remission (CR) or a partial remission (PR), marrow response, or clinical benefit as defined by the MDS/MPN IWG 2015 criteria. In the AML cohort, backfilling may begin once at least one participant has achieved a response defined by ELN 2022 criteria. Dose expansion will occur upon completion of dose escalation in each cohort, using a Simon 2-stage adaptive design. Approximately 47 CMML and 58 AML patients may be enrolled in this phase 1 study. The primary objectives of the study are to evaluate the safety and tolerability of STX-0712 and to determine the minimal safe and biologically effective dose, recommended phase 2 dose (RP2D), and/or maximum tolerated dose (MTD), and to characterize dose-limiting toxicities (DLTs). Secondary objectives include evaluation of preliminary antitumor activity, pharmacokinetic (PK) parameters, and pharmacodynamic effects of STX-0712 on CCR2+ malignant cells in blood and bone marrow. Key exploratory endpoints include: (1) assessment of changes in CCR2+ tumor cells following STX-0712 dosing, (2) evaluation of candidate biomarkers, (3) characterization of T cells, B cells and NK cells at baseline and over the course of treatment, and (4) to explore the effects of STX-0712 on patient-reported outcomes using the CMML Symptoms Assessment Tool (MPN-SAF-TSS scoring system) and the EuroQoL 5 Dimension 5 level (EQ-5D-5L) for AML. Enrollment for Cohort 1 (CMML) began in March 2025, and the study is ongoing. Clinical Trial Information: NCT06950034