Biosplice has initiated dosing in an NCI-sponsored Phase 1 study of cirtuvivint in relapsed/refractory AML and MDS, testing the selective pan-CLK/pan-DYRK inhibitor as monotherapy and in combination with the oral hypomethylating agent decitabine/cedazuridine (ASTX727). The ETCTN-run trial (NCT06484062) will characterize safety, PK/PD, and early activity in a post-standard-of-care population, with Dana-Farber as the lead site under a CRADA with NCI’s CTEP.
The move advances a splicing-modulation strategy into hematologic malignancies where resistance after venetoclax- and HMA-based regimens remains a bottleneck. CLK/DYRK inhibition is intended to reprogram alternative RNA splicing and suppress oncogenic isoforms, a mechanistic angle distinct from direct pathway inhibition or targeted degradation. Pairing with oral decitabine/cedazuridine aligns with current practice patterns. It could amplify cytotoxic pressure through epigenetic priming plus splicing perturbation, while keeping the regimen outpatient and operationally simpler than parenteral backbones. The monotherapy arm offers a clean pharmacology readout and a baseline for combination deltas.
Strategically, anchoring early hematology development inside NCI’s network is a capital-efficient way to generate human proof-of-mechanism and de-risk dose selection before company-run expansions. It also signals institutional confidence in a modality that has seen uneven translation in prior splicing-focused programs. For Biosplice, which has advanced cirtuvivint through first-in-human and early combination studies in solid tumors and maintains a late-stage non-oncology asset, the hematology entry broadens optionality while leveraging a single small-molecule platform. The choice of an approved, oral HMA as the first combination partner is pragmatic: it mitigates enrollment friction, simplifies site logistics, and avoids early reliance on proprietary co-development.
For sites, this design brings the usual ETCTN advantages of centralized startup and established governance, but it will be sample-intensive. Expect serial marrow collections and transcriptomic PD assays to confirm splice modulation in leukemic blasts, with attendant scheduling and shipping complexity and the need for tight coordination with central labs. Safety management will hinge on distinguishing disease-related cytopenias from treatment-emergent myelosuppression, especially in the combination arm. Academic centers running menin inhibitor or post-venetoclax salvage studies will triage overlapping populations; an all-oral regimen and minimal infusion chair time may help recruitment, but the absence of molecular preselection could dilute early response signals. For CROs, opportunities are limited given NCI sponsorship, while omics vendors and specialty central labs stand to benefit if PD readouts become gating criteria.
Near-term read-throughs will be pharmacodynamic: clear, dose-related splice-switching in target transcripts and evidence of on-target apoptosis will matter as much as early CR/CRi in a heavily pretreated cohort. The inflection point is the RP2D, and whether tolerability with ASTX727 supports moving into venetoclax-exposed segments where unmet need and comparator benchmarks are well defined. Watch for the program’s biomarker posture—if exploratory signatures emerge, subsequent cohorts may shift to enriched designs to sharpen signal detection. Longer term, the strategic question is whether cirtuvivint aligns with HMAs alone or progresses to triplets with venetoclax, which would raise both efficacy expectations and the management burdens of hematologic toxicity. Timelines to initial PD/safety data and clarity on expansion cohorts will determine whether Biosplice prioritizes AML/MDS within a pipeline that also spans soft tissue sarcoma and planned solid tumor combinations.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
