Abstract
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.
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.
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.
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.
NCT02841540. 22 July 2016
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•H3B-8800 showed promising preliminary results in LR-MDS with SF3B1 mutations and transfusion-dependent anemia.•However, two expansion cohorts did not confirm transfusion independence response in the same patient population.•Toxicities were manageable; daily dosing AE profile was similar to previously reported intermittent cyclicl dosing.•Intermittent dosing could be further investigated as a way to decrease dose reductions and early discontinuations.