H3B-8800-G0001-101: A first in human phase I study of a splicing modulator in patients with advanced myeloid malignancies.

Abstract

TPS7075 Background: Dysregulated mRNA splicing is important in tumorigenesis and in resistance to cancer therapy. Somatic heterozygous mutations in core spliceosome genes (e.g. SF3B1, SRSF2, U2AF1) have been reported at high frequencies in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML). These mutations confer a change of function resulting in aberrant mRNA splicing that, in preclinical models, results in defects in hematopoietic cell development and myelodysplasia. Recurrent mutations in the spliceosome of patients with malignancies suggests importance in disease pathogenesis. Cells bearing splicing mutations depend on wild-type spliceosome function, suggesting the spliceosome as a therapeutic target. In vitro data indicate preferential induction of apoptosis (measured by caspase 3/7 activation) in SF3B1-mutant cells following treatment with the SF3B1 modulator H3B-8800. H3B-8800 inhibits growth in human AML cell lines, including those with mutations in U2AF1, SRSF2 or SF3B1. Oral administration of H3B-8800 modulates splicing and induces antitumor activity in xenograft leukemia models expressing mutant core spliceosome components. Methods: This study explores the safety of H3B-8800 in patients with myeloid cancers. Dose escalation (Cohort A) follows a 3+3 design with a starting dose of 1 mg daily for 5 consecutive days every 14 days in a 28 day cycle. Cohort A is open to patients with MDS, AML or CMML, irrespective of spliceosome mutations. In parallel to dose escalation, up to 6 patients with mutations of interest may be enrolled at doses determined to be safe in Cohort A (Cohort B). After determining the recommended phase 2 dose, 4 expansion cohorts will enroll patients with: (1) International Prognostic Scoring System (IPSS) low/int-1 risk MDS with SF3B1 mutations, (2) IPSS low/intermediate risk-1 MDS with mutations in SRSF2, U2AF1, or ZRSR2, (3) high/intermediate risk-2 MDS or AML, and (4) CMML; 3 and 4 having mutations in SF3B1, SRSF2, U2AF1, or ZRSR2. The first cohort enrolled 3 patients and the trial is currently enrolling patients at the second dose level. Clinical trial information: NCT02841540.