A Phase 1, Open-Label, Dose Escalation and Dose Expansion Study of Cln-049 for the Treatment of Acute Myeloid Leukemia Patients with Measurable Residual Disease

Background: Substantial unmet medical need remains for patients with acute myeloid leukemia (AML) who often have minimal residual disease (MRD) at the end of induction therapy that drives disease recurrence. Emerging approaches to improve outcomes include application of novel targeted and immunotherapies to erradicate MRD in AML patients at high risk of relapse. CLN-049 is a humanized bispecific antibody, with dual binding specificities for FLT3 and CD3, on a human immunoglobulin G1 backbone with a silenced Fragment crystallizable domain. CLN-049 effectively redirects CD3+ T cells to kill FLT3-expressing AML cells within the blood and bone marrow to exert anti-leukemic effect. Study Design and Methods: This is a phase 1, open-label, multicenter, dose escalation and dose expansion study to evaluate the safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of subcutaneously (SC) and intravenously (IV) administered CLN-049 in adult patients (≥ 18 years of age) with a diagnosis of AML in CR with positive MRD. Other key inclusion criteria include: patients who have exhausted or are ineligible to receive available treatment alternatives or are expected to receive alternative therapy (e.g. allo-HSCT) at a later date, and ECOG Performance Status 0-1. Key exclusion criteria include prior treatment with chimeric antigen receptor (CAR-T) cell therapy or other modified T cell therapy, FLT3-directed bispecific molecule, FLT3-targeted antibody, or allo-HSCT within 60 days of treatment. The study consists of an initial dose escalation phase commencing with accelerated titration in single-patient cohorts followed by a standard 3+3 dose escalation design exploring both SC and IV routes of administration to identify the maximum tolerated dose (MTD), or maximum administered dose if no MTD is defined. A subsequent dose expansion phase will further characterize the safety and preliminary efficacy of CLN-049 in this patient population at the dose, schedule, and preferred route of administration determined in dose escalation phase to allow determination of a RP2D. CLN-049 will be administered every 7 days in 21-day cycles until morphologic relapse, unacceptable toxicity, proceeding to alternative treatment (eg, allo-HSCT), or a maximum of 12 weeks of treatment. The initial administration of CLN-049, including potential step-up doses and the first target dose, will be administered on an inpatient basis. Subsequent doses may be given in the outpatient setting. Safety, PK, PD, and preliminary efficacy assessments will guide the dose selection and schedule for further evaluation. The primary endpoint is safety. Key secondary endpoints include the proportion of patients achieving MRD negativity, time to MRD negativity, duration of MRD negativity, time to disease progression (MRD or morphologic relapse), time to subsequent anti-leukemia therapy, progression-free survival, overall survival, PK, and anti-drug antibodies. Approximately 70 patients (50 in dose escalation and 20 in dose expansion) will be enrolled at 12 sites in Germany and Spain, including both community and academic centers. The study is currently enrolling in Germany and Spain (EU CT: 2023-506572-27-00).