Paper Details

ABSTRACT

Background and Significance: 

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by clonal expansion of immature myeloid blasts, progressive bone marrow failure, and poor long-term survival. The median age of AML onset is 70, and elderly or unfit patients (pts) have poor tolerance for intensive chemotherapy (IC). The combination of the hypomethylating agent azacitidine (aza) and the BCL-2 inhibitor venetoclax (ven) is the standard of care (SOC) in pts >75 years old or those with significant comorbidities. However, response rates and durability are heterogeneous, particularly in pts with high-risk genetic disease, and the estimated 5-year overall survival rate for AML remains <10% in pts older than 60. These persistent therapeutic limitations underscore the need for novel treatment strategies capable of achieving deeper, more durable remissions while maintaining tolerability in this predominantly older pt population. 

CLN-049 is a humanized bispecific T-cell engager with dual binding specificities for FLT3 (wild-type and mutant forms) and CD3 on a human IgG1 backbone. FLT3 is a compelling cell surface target for immunotherapy, being expressed on >80% of AML blasts but only on a limited number of normal hematopoietic precursors and dendritic cells. In preclinical studies, CLN-049 effectively redirected T cells to kill FLT3-expressing AML blasts within the peripheral blood and bone marrow. CLN-049 has demonstrated promising anti-leukemic activity in a broad, heavily pretreated population of pts with relapsed/refractory AML or myelodysplastic syndrome in CLN-049-001 (NCT05143996), a phase 1 multiple ascending dose study evaluating intravenous (IV) CLN-049 monotherapy (Abdul-Hay et al, ASH 2025). At the highest tested target dose of 12 µg/kg, the composite complete remission (CRc; complete remission [CR]/CR with partial or incomplete hematologic recovery [CRh/CRi]) rate was 31% (5/16 pts), including 2 pts with flow measurable residual disease (MRD)-negative CRc. Responses were independent of baseline genetic risk, with many responses durable beyond 16 weeks and/or allowing transition to allogeneic stem cell transplantation (allo-SCT). There were no dose-limiting adverse events observed at the highest target dose in regimens utilizing 2 step-up doses (SUDs). Notably, no ≥ Grade 3 cytokine release syndrome (CRS) events occurred. The favorable safety profile and single-agent activity of CLN-049 provide a strong rationale for combining it with the current standard-of-care regimen of aza/ven. Furthermore, preclinical data suggest that aza/ven may enhance T-cell activity, leading to potential biological synergy with CLN-049. 

Study Design and Methods: 

CLN-049-AML-103 (NCT07722767) is a phase 1b, multicenter, open-label, 3+3 dose-escalation and dose-expansion study to evaluate the safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of IV CLN-049 in combination with aza/ven. Pts with newly diagnosed AML who are either considered unfit for IC or are candidates for lower-intensity therapy because of adverse-risk disease biology will be enrolled. Prior cytoreductive therapy with hydroxyurea is permitted to ensure white blood cell count of ≤20,000/μL by cycle (C) 1, day (D) 1. Testing for FLT3 expression prior to study entry is not required. 

Pts will receive aza (D1–7) and ven (D1–28) in 28-day cycles starting on C1D1. In the first induction cycle, 2 initial CLN-049 SUDs (D8 and D11) will be utilized to mitigate the risk of CRS, before administration of the full target dose on C1D15 and weekly thereafter. Pts who have not achieved morphological remission at the end of the first induction cycle may repeat induction for up to 4 cycles. Pts achieving morphological remission will transition to consolidation (reduction in ven dosing frequency to D1–14) and potentially maintenance (reduction in CLN-049 dosing frequency to every 2 weeks, contingent on attainment of MRD negativity). 

Safety, PK, PD, and preliminary efficacy assessments will guide the dose selection and schedule. The primary endpoint is safety and recommended phase 2 dose regimen selection. Key secondary endpoints include PK parameters, immunogenicity measurements, as well as preliminary efficacy as assessed by clinical response, survival, MRD negativity, and proportion of pts proceeding to allo-SCT. This study is anticipated to enroll up to 54 pts at up to 10 sites throughout the United States.