Phase 1 first-in-human dose-expansion study of the oral SF3B1 modulator H3B‑8800 in lower-risk myelodysplastic syndrome.
Journal
Leukemia research
Journal Volume
156
Start Page
Article number 107735
ISSN
1873-5835
Date Issued
2025-09
Author(s)
Foran, James M
Sanz, Guillermo F
Watts, Justin M
Brunner, Andrew M
Fossard, Gaelle
Della Porta, Matteo Giovanni
Garcia-Manero, Guillermo
Dimicoli-Salazar, Sophie
Fletcher, Luke
Kim, Yoo Jin
Font, Patricia
Alfonso-Piérola, Ana
Alonso-Dominguez, Juan Manuel
Benton, Christopher
Hong, Junshik
Malcovati, Luca
Mazure, Dominiek
Lee, Je-Hwan
Yeh, Su-Peng
Goursaud, Laure
Barcellini, Wilma
Wu, Elaine
Corzo, Deyanira
Kuida, Keisuke
Stone, Richard M
Abstract
Objective: To assess the efficacy and safety of H3B-8800 at two dose regimens in patients with transfusion-dependent lower-risk myelodysplastic neoplasms (LR-MDS) with somatic SF3B1 mutations. Methods: In this Phase 1 multicenter study, adults with LR-MDS with SF3B1 mutations were enrolled in two expansion cohorts: 10 mg and 5 mg twice a day (BID). Patients were red blood cell (RBC) transfusion-dependent, defined as ≥ 4 RBC units in 8 weeks in cohort 1 and ≥ 3 RBC units in ≥ 2 transfusions in 16 weeks in cohort 2 (patients naïve to hypomethylating agents and lenalidomide). The primary endpoint was RBC transfusion independence (TI) ≥ 8 weeks. Adverse events (AEs) during treatment were assessed in each dose cohort. Results: In cohort 1 (n = 7), the H3B-8800 starting dose was reduced to 5 mg BID in the last two patients due to thrombocytopenia; this dose was selected for cohort 2 (n = 36). The median number of 28-day cycles on therapy was 2.7 and 4.8, with dose adjustments due to AEs in five (71.4 %) and 25 (69.4 %) patients in cohorts 1 and 2, respectively. The most frequently experienced AE was diarrhea. Two (28.6 %) patients in cohort 1 and seven (19.4 %) in cohort 2 developed atrial fibrillation. Two patients in each cohort achieved one interval of RBC-TI ≥ 8 weeks. Conclusion: The AE profile was similar to that reported previously, with a slightly higher incidence of atrial fibrillation. However, the low RBC-TI rate suggests insufficient efficacy of H3B-8800 at the dose levels tested. Further exploration of dosing schedules is warranted.
Subjects
Myelodysplastic syndrome
SF3B1
clinical trial
spliceosome
Type
journal article