Abstract
Background: Dysregulated alternative splicing (AS) is hallmark of cancer which plays an important role in regulating proliferation, apoptosis, immune surveillance, and therapeutic resistance. Components of the spliceosome machinery are frequently mutated in myeloid malignancies occurring in ~40-85% of MDS cases, and 10‒25% of AML cases. Furthermore, aberrant AS patterns are also frequently demonstrated in AML even in the absence of somatic spliceosome mutations and genetic screens have shown that the loss of splicing factors sensitizes AML to the BCL2 inhibitor venetoclax. CDC-like kinases (CLKs) are key regulators of AS through modulation of phosphorylation of serine/arginine rich splicing factors (SRSFs). Accordingly, modulation of aberrant alternative splicing through inhibition CLKs is a potentially promising new therapeutic paradigm for the treatment of hematologic malignancies and to address resistance to standard of care therapies.
BH-30236 is a novel, orally bioavailable, ATP-competitive, macrocyclic CLK inhibitor. At clinically relevant concentrations, BH-30236 also inhibits proviral integration for the Moloney murine leukemia virus 3 kinase (PIM3), FMS-like tyrosine kinase 3 (FLT3), and dual-specificity tyrosine-regulated kinase (DYRK) 1/2. BH-30236 potently suppressed SRSF phosphorylation and downregulated SRSF RNA and protein expression levels via non-sense mediated RNA decay (NMD). BH-30236 demonstrated in vitro efficacy in the nanomolar range across immortalized and patient-derived AML cells, including cells insensitive to venetoclax. BH-30236 was more potent than gilteritinib in inhibition of FLT3-ITD, downregulated total FLT3 expression level via NMD and led to more durable responses compared to gilteritinib in pre-clinical models of mFLT3 AML. BH-30236 also modulated DNA repair pathway and apoptosis families, leading to enhanced cancer cell apoptosis via splicing regulation. Furthermore, BH-30236 demonstrated profound in vitro and in vivo synergy with venetoclax and the combination of BH-30236 with venetoclax demonstrated substantially better efficacy than standard of care venetoclax + azacytidine in venetoclax resistant CDX AML models.
This first-in-human trial evaluates BH-30236 as monotherapy or in combination with venetoclax in patients with relapsed or refractory AML or higher risk (HR) 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-leukemic activity of BH-30236 alone or in combination with venetoclax. Enrollment in dose escalation is proceeding according to a Bayesian Optimal Interval (BOIN) design to determine recommended doses for expansion (RDEs). Dose escalation of BH-30236 in combination with venetoclax will proceed in parallel with monotherapy dose escalation also according to a BOIN design. Backfilling is permitted at dose levels where preliminary anti-leukemia activity is observed or where sufficient PK exposure has been demonstrated for select populations (eg mFLT3+). Phase 1b dose expansion will further characterize the safety, PK, PD, and preliminary efficacy in monotherapy or combination with venetoclax to determine the recommended phase 2 dose (RP2D). BH-30236 is administered as an oral continuous QD dose until disease progression or unacceptable toxicity in 28-day cycles. For combination arms, venetoclax is administered at a target dose of 400mg QD for 15-28 days per cycle. 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.