KB-Lanra 1001: A Phase 1b/2 Study of Safety, PK, PD, and Preliminary Efficacy of the Selective SYK Inhibitor Lanraplenib in Combination with the FLT3 Inhibitor Gilteritinib in FLT3-Mutated R/R AML

Topic: 4. Acute myeloid leukemia - Clinical Background: In acute myeloid leukemia (AML), Spleen Tyrosine Kinase (SYK) serves as a relay to an oncogenic transcriptional regulatory network (TRN) linked to HOXA9 and MEIS1 and, as such, helps to to suppress myeloid progenitor maturation and promotes proliferation. SYK also cooperates with internal tandem duplication (ITD)-mutated FMS-like tyrosine kinase 3 (FLT3) to drive leukemogenesis. Lanraplenib (LANRA) is an oral, potent, selective, next-generation SYK inhibitor with a 24-hour half-life, once-daily (QD) dosing, and no known drug interactions. In preclinical studies, the combination of LANRA and the FLT3 inhibitor gilteritinib shows strong antileukemic effects ex vivo, results in deeper responses, and extends overall survival in FLT3 ITD-driven AML patient-derived xenograft mouse models (Carvajal L, et al Blood 2022; 140 (Supplement 1): 5932–5933). LANRA is currently being evaluated in combination with gilteritinib in patients with relapsed or refractory (R/R) FLT3-mutated AML in the KB-LANRA 1001 trial (NCT05028751). Aims: The KB-LANRA 1001 trial is designed to determine the safety and define the maximum tolerated and/or recommended Phase 2 dose (MTD/RP2D) of LANRA when combined with gilteritinib in relapsed or refractory patients (pts) with FLT3-mutated AML. Secondary outcome measures include investigating the pharmacokinetics (PK) and pharmacodynamics (PD) of LANRA and evaluating the rate of complete responses (CR) and CR with partial hematologic recovery (CRh), duration of response (DoR), event-free survival (EFS) and overall survival (OS). Key exploratory endpoints are assessments of measurable residual disease among pts who achieve CR/CRh, correlations with selected baseline biomarkers that may predict efficacy outcomes and assessment of LANRA PD properties (including target engagement) when administered alone and in combination with gilteritinib. Methods: KB-LANRA 1001 is a global, multicenter, open-label, phase1b/2 trial of LANRA in combination with standard dose gilteritinib (120mg QD) in FLT3-mutated AML pts aged ≥18 with at least 1 prior therapy. Eligible pts must have documented FLT3 mutation from a reference lab, and can have received prior therapy with a FLT3 inhibitor (including midostaurin, gilteritinib, quizartinib, or ceronlanib). Both medications will be administered daily in sequential, 28-day cycles until progression/relapse, intolerance, or failure to achieve at least a partial remission after 6 cycles. The Phase 1b component will define the MTD/RP2D of LANRA when added to gilteritinib in accordance with a 3 + 3 dose escalation design. PK and PD parameters will be characterized for LANRA monotherapy and when co-administered with gilteritinib. All decisions regarding dose escalation including declaration of the MTD will be made by a dose-escalation committee based on the prospectively defined definition of dose-limiting toxicities and other safety metrics. The Phase 2 component will further evaluate safety, PK, PD and preliminary efficacy of the combination at the LANRA RP2D. For both trial components, response assessments will be conducted on Day 1 of Cycles 2 and 3 and every 3 cycles thereafter until 2 consecutive assessments indicate CR or CRh. All pts will be followed for relapse, EFS and OS. Results: Trial in progress. Summary/Conclusion: Accrual is ongoing. Keywords: Clinical trial, FLT3, AML, SYK