Background Common targets for T-cell–redirecting immunotherapies in AML and MDS have previously presented challenges. CLN-049 is a humanized bispecific T-cell engager with dual binding specificities for FLT3 (both wild-type and mutant forms) and CD3 on a human IgG1 backbone. As a cell surface target for immunotherapy, FLT3 is expressed on >80% of AML blasts but on only a limited number of normal hematopoietic precursors and dendritic cells. In preclinical studies, CLN-049 effectively redirects T cells to kill FLT3-expressing AML blasts within the blood and bone marrow (BM). We report results from a phase 1 multiple ascending dose study evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of intravenously (IV) administered CLN-049 in patients (pts) with R/R AML and MDS (NCT05143996).

Methods Pts aged ≥ 18 years with R/R AML or MDS were enrolled in dose escalation, 3+3 design. Testing for FLT3 expression prior to study entry was not required. CLN-049 was dosed IV using 1 or 2 step-up doses (SUD) in the first week of treatment (D1 ± D4) before weekly administration of the higher target dose (TD) (D8 onwards). Adverse events were graded by CTCAE v5, except cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) that used Lee 2019 criteria. Response was assessed using ELN 2022 (AML) or IWG 2023 (MDS) criteria. Efficacy endpoints included complete response (CR) rate, composite complete response (CRc) rate (CR/CRi/CRh in AML or CR/CRL/CRh in MDS) and ORR (CRc + MLFS + PR). Best responses are reported.

Results

As of the June 9, 2025, data cut-off (DCO), 40 pts (34 AML, 6 MDS) had been enrolled across 7 cohorts (TD range 1.5–12 µg/kg). Median age was 72 years (range 25–84) with a median of 2 prior therapies (range: 1–8, AML; 1–3, MDS). Treatment-emergent adverse events (TEAEs) occurred in 95% of pts, leading to treatment withdrawal in 7.5%. All-grade (Gr) TEAEs occurring in > 10% of pts included CRS (40%), infusion-related reaction (35%), febrile neutropenia (FN), pneumonia, stomatitis, white blood cell (WBC) count decrease (17.5% each), and alanine aminotransferase increase, diarrhea, headache, hypomagnesemia, hypophosphatemia, platelet count decrease, and hypokalemia (12.5% each). Gr ≥3 TEAEs occurring in >10% of pts included FN, WBC count decrease (17.5% each), and pneumonia (12.5%). All CRS events were limited to Gr 1 or 2; the majority occurred after a SUD or TD1. One case of Gr 1 ICANS was reported in association with Gr 2 CRS after a 6 µg/kg SUD. Neither CRS nor ICANS led to treatment discontinuation. Three events of reversible transaminitis were observed in 2 pts (1 Gr 3 event at 9 µg/kg TD, 2 Gr 4 events at 12 µg/kg TD), all occurring in association with Gr 1–2 CRS. Transaminitis was restricted to pts receiving 1 SUD and was effectively mitigated by implementation of a second SUD, evidenced by 0 subsequent events in 12 pts receiving 2 SUD before the 12 µg/kg TD. At the DCO, 32 pts (29 AML, 3 MDS) were efficacy evaluable (≥1 response assessment). Anti-leukemic activity was observed at a TD of ≥ 6 µg/kg (23 pts, all AML), with a CR rate of 9% (2/23 pts), CRc rate of 30% (7/23 pts), and ORR of 57% (13/23 pts). In 9/23 pts achieving BM blasts <5%, 3 pts were MRD negative by flow cytometry; relapse was not observed in MRD-negative pts, and 1 has remained on study for > 6 months. At the highest TD studied thus far of 12 µg/kg (13 pts), CRc rate was 31% (4/13 pts), and ORR was 69% (9/13 pts). Responses were observed in pts with AML regardless of baseline genetic risk. Notably, among 5 pts with TP53-mutated AML treated at 12 µg/kg, 4 responses (2 CRh, 2 MLFS) were observed. At the doses tested, CLN-049 showed a dose-dependent increase in exposure with apparent nonlinear PK (driven by target-mediated drug disposition), moderate to high inter-subject variability, and limited accumulation. Consistent with the mechanism of action, clinical response correlated with a reduction in the frequency of FLT3-expressing blasts in the BM.

Conclusions CLN-049 demonstrated an acceptable safety profile in a broad population of pts with R/R AML and MDS. Dose levels ≥ 6 µg/kg achieved promising anti-leukemic activity, including MRD negativity, in this heavily pretreated population. Responses were also observed in pts with TP53-mutated AML, a population with a particularly poor prognosis. Dose escalation continues in this ongoing study.

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2025
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