Background and Significance:

FMS-like tyrosine kinase (FLT3)-mutation (FLT3 mut) in patients with newly diagnosed and relapsed/refractory (R/R) acute myeloid leukemia (AML) is associated with shorter overall survival (OS) and relapse-free survival. Gilteritinib is an approved therapy for R/R FLT3 mut AML, but reduction in FLT3 mut burden and sustained efficacy are rarely achieved, thus necessitating investigation of rational therapeutic combinations to improve outcomes. Spleen Tyrosine Kinase (SYK) is a non-receptor tyrosine kinase known to regulate intracellular signaling in response to extracellular stimuli via its immunoreceptor tyrosine-based activation motif (ITAM). SYK serves as a relay to an oncogenic transcriptional regulatory network (TRN) linked to HOXA9 and MEIS1-facilitated suppression of myeloid progenitor maturation and proliferation. SYK cooperates with internal tandem duplication (ITD)-mutated FLT3 to drive leukemogenesis.

Lanraplenib (LANRA) is an oral, potent, selective, next-generation SYK inhibitor with a 24-hour half-life, and once-daily (QD) dosing. In preclinical studies, the combination of LANRA and the FLT3 inhibitor gilteritinib demonstrated strong antileukemic effects ex vivo, resulting in deeper responses, and extended overall survival in FLT3 ITD-driven AML patient-derived xenograft mouse models. LANRA in combination with gilteritinib is currently being evaluated in patients with R/R FLT3 mut AML in the KB-LANRA 1001 trial (NCT05028751).

Study Design and Methods:

KB-LANRA 1001 is a global, multicenter, open-label phase 1b/2 trial designed to determine the safety and maximally tolerated and/or recommended phase 2 dose (MTD/RP2D) of LANRA in combination with standard dose gilteritinib (120 mg QD) in patients with R/R FLT3 mut AML. Secondary endpoints include evaluating pharmacokinetics (PK), pharmacodynamics (PD), and response evaluation (complete response (CR), CR with partial hematologic recovery (CRh), duration of response (DoR), event-free survival (EFS) and OS of the combination. Key exploratory endpoints include reduction of FLT3 mutvariant allele frequency among patients who achieve CR/CRh, correlation with selected baseline biomarkers that may predict efficacy outcomes, and assessment of LANRA PD properties (including target engagement).

Eligibility requirements include documented FLT3 mut (ITD, tyrosine kinase domain [TKD] or both), age ≥18, and receipt of at least 1 prior therapy. Oral LANRA + gilteritinib will be administered daily until progression/relapse, intolerance, or failure to achieve at least a partial response (PR) after 6 cycles. The phase 1b component will follow a 3+3 dose escalation design. A dose-escalation committee (DEC) will decide LANRA dose escalation based on prospectively defined definitions of dose-limiting toxicity and safety metrics. Enrollment of additional patients to dose cohort(s) previously cleared for safety and tolerability by the DEC will be allowed under specific conditions.

The phase 2 component will further evaluate safety, PK, PD, and anti-leukemic activity of the combination at the LANRA RP2D

Arnan:Kronos Bio: Research Funding. Patel:BMS: Honoraria; AbbVie: Honoraria; Kronos Bio: Research Funding; Pfizer: Research Funding. Esteve:Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Gilead: Consultancy; Astellas: Consultancy; Pfizer: Research Funding; Kronos Bio: Research Funding. Schiller:Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding, Speakers Bureau; Astellas Pharma: Consultancy, Research Funding, Speakers Bureau; Kite: Research Funding, Speakers Bureau; Stemline Therapeutics: Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Karyopharm Therapeutics: Research Funding, Speakers Bureau; Actinium Pharmaceuticals: Research Funding; Actuate Therapeutics: Research Funding; Arog: Research Funding; Celator: Research Funding; Constellation Pharmaceuticals: Research Funding; Daiichi Sankyo: Research Funding; Deciphera: Research Funding; Delta-Fly Pharma: Research Funding; FORMA Therapeutics: Research Funding; Fujifilm: Research Funding; Gamida Cell: Research Funding; Genentech/Roche: Research Funding; Geron: Research Funding; Mateon Therapeutics: Research Funding; Onconova Therapeutics: Research Funding; Pfizer: Research Funding; Precog: Research Funding; REGiMMUNE: Research Funding; Samus Therapeutics: Research Funding; Sangamo Bioscience: Research Funding; Sellas Life Sciences: Research Funding; Stemline Therapeutics: Research Funding; Takeda: Research Funding; Tolero Pharmaceuticals: Research Funding; Trovagene: Research Funding; Agios: Research Funding; ElevateBio: Research Funding; Ono Pharmaceutical: Research Funding; AVM Biotechnology: Research Funding; Syros Pharmaceuticals: Research Funding; Kronos Bio: Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Agios: Consultancy; Ono Pharmaceutical: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company, Research Funding; Bristol Myers Squibb: Current equity holder in publicly-traded company, Research Funding, Speakers Bureau. Swords:Kronos Bio: Research Funding. Alonso-Dominguez:Kronos Bio: Research Funding; GlaxoSmithKline: Research Funding; Astrazeneca: Research Funding; AVM Biotech: Research Funding; OnoPharma: Research Funding; Novartis: Current equity holder in private company, Other: Travel/Accommodations/Expenses, Research Funding; Bristol Myers Squibb: Research Funding; Amgen: Research Funding; Incyte: Research Funding; Pfizer: Other: Travel/Accommodations/Expenses, Research Funding; Celgene: Research Funding; Astellas: Consultancy, Research Funding. Michaelis:Celgene Corporation: Consultancy; Sierra Oncology: Consultancy; Incyte Corporation: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Sierra oncology: Consultancy; NKARTA: Consultancy. Daver:FATE: Research Funding; Shattuck Labs: Consultancy; Agios: Consultancy; Glycomimetics: Research Funding; Syndax: Consultancy; AROG: Consultancy; Trillium: Consultancy, Research Funding; Novimmune: Research Funding; Novartis: Consultancy; Jazz: Consultancy; Hanmi: Research Funding; AbbVie: Consultancy, Research Funding; Trovagene: Research Funding; ImmunoGen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Kite, a Gilead company: Consultancy, Research Funding; Kronos Bio: Research Funding. Carvajal:Kronos Bio: Current Employment, Current equity holder in publicly-traded company. Bray:Kronos Bio, Inc.: Consultancy. Olek:Kronos Bio, Inc.: Current Employment. Cutler:Kronos Bio, Inc.: Current Employment. DiMartino:Kronos Bio, Inc.: Current Employment. Stein:Blueprint: Consultancy; Eisai: Research Funding; CTI Biopharma: Consultancy; OnCusp: Consultancy; Syndax: Consultancy; Gilead: Consultancy; Neoleukin: Consultancy; Foghorn: Consultancy; Calithera: Consultancy; Servier: Consultancy; Daiichi: Consultancy; Aptose: Consultancy; Syros: Consultancy; Astellas: Consultancy; Ono Pharma: Consultancy; Bristol Myers Squib: Consultancy, Research Funding; Novartis: Consultancy; PinotBio: Consultancy; Janssen: Consultancy; Agios: Consultancy; Jazz: Consultancy; Menarini: Consultancy; Genentech: Consultancy; Abbvie: Consultancy; Genesis: Consultancy.

2023
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