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Phase I first-in-human dose escalation study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms

Autores: 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-Domínguez, J. M.; Alfonso Piérola, Ana; Coombs, C. C.; Deeg, H. J.; Flinn, I.; Foran, J. M.; García-Manero, G.; Maris, M. B.; McMasters, M.; Micol, J. B.; De Oteyza, J. P.; Thol, F.; Wang, E. S.; Gourineni, V.; Watts, J. M. ; Taylor, J.; Stone, R.; Gourineni, V.; Marino, A. J.; Yao, H. L. ; Destenaves, B.; Yuan, X. B.; Yu, K.; Dar, S.; Ohanjanian, L.; Kuida, K.; Xiao, J. J.; Scholz, C.; Gualberto, A. (Autor de correspondencia); Platzbecker, U. (Autor de correspondencia)
Título de la revista: LEUKEMIA
ISSN: 0887-6924
Volumen: 35
Número: 12
Páginas: 3542 - 3550
Fecha de publicación: 2021
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.