PS1034 PHASE I DOSE ESCALATION CLINICAL TRIAL OF H3B‐8800, A SPLICING MODULATOR, IN PATIENTS WITH ADVANCED MYELOID MALIGNANCIES
Authors: D. Steensma, V. Klimek, J. Yang, A. Brunner, P. Font Lopez, P. Greenberg, M. Maris, S. Buonamici, A. Kim, A. Marino, J. Schindler, S. Smith, H. Yao, K. Yu, U. Platzbecker
Journal: HemaSphere (2019)

Background: Somatic heterozygous mutations in core spliceosome genes (e.g. SF3B1, SRSF2, U2AF1, ZRSR2 ) are frequently detected in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML), suggesting their importance in disease pathogenesis. Malignant cells bearing spliceosome mutations depend on remaining wild‐type spliceosome function for survival, making the spliceosome complex a potential therapeutic target. Previously, we have shown that H3B‐8800, an oral small‐molecule splicing modulator that binds to SF3B1, induces antitumor activity in xenograft leukemia models with core spliceosome mutations. Aims: This dose escalation clinical trial explores the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of H3B‐8800 in patients with myeloid malignancies to identify the recommended phase 2 dose. Methods: Dose escalation cohorts, which employ a standard 3+3 design, are examining two different once daily dosing regimens (Schedule I: 5 days on/9 days off; Schedule II: 21 days on/ 7days off) in a 28‐day cycle, with stratification based on low‐risk (LR) versus high‐risk (HR) myeloid diseases. Results: As of November 7, 2018, 59 patients were enrolled in dose escalation cohorts with dose ranging from 1–30 mg, on the 5 days on/9 days off schedule. The patient population included AML (n = 22), CMML (n = 3), HR‐MDS (n = 12), LR‐MDS (n = 21) and 1 MDS with unknown risk level. Most patients (93%) had spliceosome mutations of interest. Most common mutations were SRSF2 p.P95H (n = 13), SF3B1 p.K700E (n = 10), SF3B1 p.R625C (n = 4), and SRSF2 p.P95_R102Del (n = 4). H3B‐8800 has thus far been well tolerated with one dose‐limiting toxicity (bone marrow aplasia) observed in a low‐risk MDS patient at 7 mg on schedule I. Most adverse events were Grade 1/2. Common treatment‐related adverse events (&gt;10%) include diarrhea, nausea, vomiting, and fatigue. Preliminary PK indicates that H3B‐8800 is rapidly absorbed, exhibits dose‐proportional increase in plasma exposure, and similar exposure after a single dose or repeat daily doses. Consistent dose‐dependent target engagement (i.e., alteration in mature mRNA transcripts) has been observed in peripheral blood from patients enrolled in the 2 mg and up to 30 mg dose cohorts. The magnitude of splicing modulation observed clinically is trending towards levels detected at an efficacious dose in preclinical xenograft models. Seventeen patients had time on treatment greater than 180 days. One LR‐CMML patient treated at 7 mg dose level on schedule I demonstrated hematological improvement in platelet counts, with confirmed target engagement. Summary/Conclusion: Preliminary results from this first‐in‐human trial confirm the favorable safety, PK, and PD profiles of H3B‐8800. Dose exploration is ongoing for both schedules. Clinical trial information: NCT02841540.