Abstract
Background: Alternative splicing (AS) is a primary mechanism for mRNA transcript diversification and protein expression regulation. AS is a new hallmark of cancers including acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) which plays an important role in regulating proliferation, apoptosis, immune surveillance, and therapeutic resistance. CDC-like kinases (CLK) regulate AS through modulation of phosphorylation of serine/arginine rich splicing factors (SRSFs). SRSFs are often mutated or upregulated in AML/MDS. BH-30236 is a novel, orally bioavailable, macrocyclic, ATP-competitive small molecule inhibitor of CLK1/2/4. At clinically relevant concentrations, BH-30236 also inhibits provirus integration site for Moloney leukemia virus 3 (PIM3), the dual-specificity tyrosine phosphorylation-regulated kinases 1/2 (DYRK1/2), and FMS-like tyrosine kinase 3 (FLT3). BH-30236 has demonstrated substantial anti-cancer activity in nonclinical leukemia and solid tumor models as monotherapy or in combination with standard therapies. BH-30236 not only modulated the phosphorylation of SRSFs, but also downregulated the expression of SRSFs via non-sense mediated RNA decay (NMD). BH-30236 was more potent than gilteritinib in inhibition of FLT3-ITD. Furthermore, BH-30643 downregulated FLT3 expression level via inhibition of CLK leading to NMD. Overall, BH-30236 regulated DNA repair pathway and apoptosis family, leading to cancer cell death. This first-in-human trial evaluates BH-30236 in patients with previously treated AML or higher risk MDS.
Study Design and Methods: Patients ≥18 years with previously treated (≤5 lines of systemic treatment) R/R AML or HR-MDS are eligible for this phase 1/1b, multi-center, open-label, dose escalation study (NCT06501196) to evaluate the safety, tolerability, PK, PD and preliminary anti-leukemia activity of BH-30236. Enrollment is proceeding according to an accelerated 3+3 design in which single subject cohorts followed by 3+3 escalation cohorts are enrolled to determine recommended doses for expansion (RDEs). Backfilling is permitted at dose levels where preliminary anti-leukemia activity is observed. Phase 1b dose expansion will further characterize the safety, PK, PD, and preliminary efficacy at RDEs to determine the recommended phase 2 dose (RP2D) for further development. BH-30236 is administered as a continuous QD dose until disease progression or unacceptable toxicity. Disease response assessment is performed according to European Leukemia Network or International Working Group guidelines for AML or MDS, respectively. Exploratory analyses will include assessment of measurable residual disease, longitudinal profiling of genomic alteration markers and characterization of gene expression and alternative splicing modulation in the bone marrow and/or peripheral blood. Enrollment is ongoing in the US.
Stein:Genentech: Consultancy, Other: consulting fees; Jazz Pharmaceuticals: Consultancy, Other: consulting fees; Servier: Consultancy, Other: consulting fees; Gilead: Consultancy, Other: consulting fees; Celgene: Consultancy, Other: consulting fees; Daiichi Sankyo, Inc.: Consultancy, Other: consulting fees; Astellas Pharmaceuticals: Consultancy, Other: consulting fees; AstraZeneca: Consultancy, Other: consulting fees; Agios Pharmaceuticals: Consultancy, Other: consulting fees; Abbvie: Consultancy, Other: consulting fees. Mims:Leukemia and Lymphoma Society Beat AML Study: Other: Senior Medical Director; BMS: Membership on an entity's Board of Directors or advisory committees; Daiichi Saynko: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Treadwell Therapeutics: Membership on an entity's Board of Directors or advisory committees. Watts:Rafael Pharma: Consultancy; Immune Systems Key: Research Funding; Takeda: Research Funding; Celgene/BMS: Consultancy; Reven Pharma: Consultancy; Daiichi Sankyo: Consultancy; Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Other: safety monitoring or advisory boards, Research Funding. Mannis:Gilead: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Syndax Pharmaceuticals, Inc.: Research Funding; Jazz: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Research Funding; Orbital Therapeutics: Membership on an entity's Board of Directors or advisory committees; Immunogen: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Wugen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; ImmuneOnc: Research Funding; Forty Seven: Membership on an entity's Board of Directors or advisory committees, Research Funding; Stemline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aptose: Research Funding; Macrogenics: Consultancy. Liu:Rigel: Consultancy, Other: Advisory board meeting; Servier: Consultancy, Other: Advisory board meeting; AbbVie: Consultancy. Sallman:Abbvie: Consultancy; Agios: Consultancy; Axiom: Consultancy; Gilead: Consultancy; Celyad: Consultancy; Froghorn: Consultancy; Incyte: Consultancy; Intellisphere, LLC: Consultancy; Johnson & Johnson: Consultancy; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; NextTech: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AvenCell: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; BlueBird Bio: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Jasper Therapeutics: Membership on an entity's Board of Directors or advisory committees; NKARTA: Membership on an entity's Board of Directors or advisory committees; Orbital Therapeutics: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Apera: Research Funding; Jazz: Research Funding. Ravandi:Astyex/Taiho: Research Funding; BMS: Consultancy, Honoraria; Syros: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Amgen: Research Funding; Xencor: Research Funding; Abbvie: Consultancy, Honoraria; Prelude: Consultancy, Honoraria, Research Funding. Wang:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Immunogen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Award Committee, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; NuProbe: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kura: Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Qiagen: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Speakers Bureau; UptoDate: Other: Section Editor; J&J: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of