Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms

Abstract

We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1–40 mg, n = 65) and schedule II (21 days on/7 days off, 7–20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.

Nature or Nurture? Role of the Bone Marrow Microenvironment in the Genesis and Maintenance of Myelodysplastic Syndromes

“…Although this drug has yielded promising results by generating transfusion independency [179] in up to 38% of the patients treated with the drug [180,181], more data are needed to fully understand its long-term efficacy. The use of spliceosome inhibitors (H3B-8800), at least in initial stages, provided some excitement; however, a recent report has shown low response rates with some toxicities, such as diarrhoea, nausea, fatigue, and vomiting [182]. Another drug, namely Roxadustat, an oral hypoxia-inducible factor inhibitor is currently being tested in clinical trials involving non-del(5q) low-risk MDS patients with low transfusion burden [183].…”

Investigating the Molecular Mechanism of H3B-8800: A Splicing Modulator Inducing Preferential Lethality in Spliceosome-Mutant Cancers

“…H3B has also shown a preferential antitumor activity in cell cultures and patient-derived xenograft models presenting cancerassociated mutations of SF3B1 and SRSF2 [23]. In addition, the recently concluded phase I clinical trial demonstrated that this drug candidate has an acceptable adverse effect profile and identified a subset of patients who could benefit from its treatment [24].…”

Alternative Splicing in Myeloid Malignancies

“…Small molecules have been tested in several models of spliceosome dysfunction. Specifically, H3B-8800, a selective and orally bioavailable modulator of normal and mutant SF3b complex, has shown dose-dependent modulation of splicing in pre-clinical xenograft models [ 54 ], but unfortunately, these data have not been confirmed by the phase I, first-in-human open-label, multicenter trial for patients with previously treated MDS, AML, and CMML (NCT02841540) [ 55 ]. The discovery of H3B-8800 follows a path of research efforts on natural products ( Figure 3 ).…”