Paper Details

ABSTRACT

Background 

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. We report final results from the Phase 1 dose-escalation study evaluating safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of intravenous (IV) 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 3+3 dose escalation; testing for FLT3 expression was not required prior to enrollment. CLN-049 was administered IV with 1 or 2 step-up doses (SUDs) in the first week of treatment (day [D] 1 ± D4) before weekly administration of the target dose (TD; range, 1.5–24 µg/kg) from D8 onwards. Adverse events (AEs) were graded by CTCAE v5, except cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), which used Lee 2019 criteria. Best response was assessed using ELN 2022 (AML) or IWG 2023 (MDS) criteria. Efficacy endpoints included composite complete response (CRc) rate (complete response [CR]/CR with incomplete blood count recovery/CR with partial hematologic recovery [CRh] in AML, or CR/CR with limited response/CRh in MDS) and overall response rate (ORR; CRc + morphologic leukemia-free state [MLFS] + partial response). 

Results 

As of the data cutoff, 87 pts (76 AML, 11 MDS) were enrolled across 13 cohorts (TD range, 1.5–24 µg/kg). Median age was 71 years (range, 25–89), with a median of 2 prior therapies (range, 1–8 [AML]; 1–3 [MDS]). All-grade (Gr) treatment-emergent AEs (TEAE) occurring in >15% of pts included infusion-related reaction (47%), CRS (35%), elevated ALT (28%) and AST (22%), febrile neutropenia (FN, 18%), hypokalemia (18%), and increased white blood cell count (16%). Most CRS events were Gr1/2 and occurred within the first 2 weeks of therapy. The CRS rate was 36% (13/36 pts), including the only Gr3 event, in pts receiving 1 SUD. Implementation of a 2-SUD regimen (1 or 1.5 µg/kg SUD1, 6 µg/kg SUD2) reduced CRS incidence (26%, 7/27) and severity (Gr1/2 only); increasing SUD1 to ≥3 µg/kg raised the CRS rate (42%, 10/24). ICANS was uncommon (6%, 5/87), with 1 Gr3 event, and all events were self-limiting. Gr ≥3 TEAEs occurring in >10% of pts included FN (18%), transaminase (TA) elevations (14%), and pneumonia (12%). Utilization of a 2-SUD regimen with a SUD1 of 1 or 1.5 µg/kg mitigated TA elevations (4%, 1/27). Importantly, TA elevations were asymptomatic, reversible, and not associated with other liver lab abnormalities. TEAEs led to treatment withdrawal in 15% of pts. 

Eighty pts were efficacy evaluable (≥1 response assessment or pts who discontinued without assessment). Anti-leukemic activity was observed at the 6 µg/kg TD, with CRc rate of 19% (3/16, all CR) and ORR of 25% (4/16, no MLFS). At the 12 µg/kg TD, CRc rate was 21% (6/29, 2 CR) and ORR was 45% (13/29, 2 MLFS); in pts treated at the 12 µg/kg TD who received a starting SUD of 1.5 µg/kg or lower, CRc rate was 26% (5/19, 2 CR) and ORR was 53% (10/19, 1 MLFS). Escalation to doses ≥18 µg/kg maintained ORR of 32% (6/19); however, this was mostly MLFS (3/19), with CRc rate of 5% (1/19), highlighting the potential for higher doses to delay hematopoietic recovery. Responses were also observed in TP53 mutated pts at 12 µg/kg, with CRc rate of 17% (2/12) and ORR of 33% (4/12, 1 MLFS); at doses ≥18 µg/kg, ORR was 38% (3/8, all MLFS). Measurable residual disease–negative responses by multiparameter flow cytometry were observed in 5 pts across all efficacious TDs. Two responding pts remained on CLN-049 treatment for >12 mo without further consolidation; in 4 additional responding pts, CLN-049 provided a bridge to allogeneic hematopoietic stem cell transplantation. 

CLN-049 exposure increased in a dose-dependent manner, with nonlinear PK consistent with target-mediated clearance. Increases in T-cell activation (by flow cytometry) were observed following treatment with CLN-049 and were greater in pts with responses.  

Conclusions 

Phase 1 evaluation of CLN-049 demonstrated that a 2-SUD regimen on D1 (1.5 µg/kg) and D4 (6 µg/kg) provided optimal immune priming and favorable clinical safety. Highest CRc rates were observed at TDs of 6 or 12 µg/kg. These TDs demonstrated anti-leukemic activity with count recovery in a broad population of pts with R/R AML or MDS, including those with TP53 mutations, to be further explored in an upcoming Phase 2 study.