PHASE I DOSE ESCALATION CLINICAL TRIAL OF H3B-8800, A SPLICING MODULATOR, IN PATIENTS WITH ADVANCED MYELOID MALIGNANCIES
Author(s): ,
David Steensma
Affiliations:
Dana Farber Cancer Institute,Boston,United States
,
Virginia Klimek
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Jay Yang
Affiliations:
Barbara Ann Karmanos Cancer Institute,Detroit,United States
,
Andrew Brunner
Affiliations:
Massachusetts General Hospital,Boston,United States
,
Patricia Font Lopez
Affiliations:
Hospital General Universitario Gregorio Marañón,Madrid,Spain
,
Peter Greenberg
Affiliations:
Stanford Cancer Center,Stanford,United States
,
Michael Maris
Affiliations:
SCRI-Colorado Blood Cancer Institute,Denver,United States
,
Silvia Buonamici
Affiliations:
H3 Biomedicine,Cambridge,United States
,
Amy Kim
Affiliations:
H3 Biomedicine,Cambridge,United States
,
Alyssa Marino
Affiliations:
H3 Biomedicine,Cambridge,United States
,
Joanne Schindler
Affiliations:
H3 Biomedicine,Cambridge,United States
,
Sherri Smith
Affiliations:
H3 Biomedicine,Cambridge,United States
,
Huilan Yao
Affiliations:
H3 Biomedicine,Cambridge,United States
,
Kun Yu
Affiliations:
H3 Biomedicine,Cambridge,United States
Uwe Platzbecker
Affiliations:
Universitätsklinikum Leipzig,Leipzig,Germany
EHA Library. Steensma D. Jun 15, 2019; 266651; PS1034
Prof. David Steensma
Prof. David Steensma
Contributions
Abstract

Abstract: PS1034

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

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 (>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 7mg dose level on schedule I demonstrated hematological improvement in platelet counts, with confirmed target engagement.

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.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): MDS/AML, Mutation analysis, Phase I

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