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Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms. Leukemia Steensma, D. P., Wermke, M., Klimek, V. M., Greenberg, P. L., Font, P., Komrokji, R. S., Yang, J., Brunner, A. M., Carraway, H. E., Ades, L., Al-Kali, A., Alonso-Dominguez, J. M., Alfonso-Pierola, A., Coombs, C. C., Deeg, H. J., Flinn, I., Foran, J. M., Garcia-Manero, G., Maris, M. B., McMasters, M., Micol, J., De Oteyza, J. P., Thol, F., Wang, E. S., Watts, J. M., Taylor, J., Stone, R., Gourineni, V., Marino, A. J., Yao, H., Destenaves, B., Yuan, X., Yu, K., Dar, S., Ohanjanian, L., Kuida, K., Xiao, J., Scholz, C., Gualberto, A., Platzbecker, U. 2021

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 1-40mg, n=65) and schedule II (21 days on/7 days off, 7-20mg, 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.

View details for DOI 10.1038/s41375-021-01328-9

View details for PubMedID 34172893