TY - JOUR
T1 - Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms
AU - Steensma, David P.
AU - Wermke, Martin
AU - Klimek, Virginia M.
AU - Greenberg, Peter L.
AU - Font, Patricia
AU - Komrokji, Rami S.
AU - Yang, Jay
AU - Brunner, Andrew M.
AU - Carraway, Hetty E.
AU - Ades, Lionel
AU - Al-Kali, Aref
AU - Alonso-Dominguez, Juan M.
AU - Alfonso-Piérola, Ana
AU - Coombs, Catherine C.
AU - Deeg, H. Joachim
AU - Flinn, Ian
AU - Foran, James M.
AU - Garcia-Manero, Guillermo
AU - Maris, Michael B.
AU - McMasters, Malgorzata
AU - Micol, Jean Baptiste
AU - De Oteyza, Jaime Perez
AU - Thol, Felicitas
AU - Wang, Eunice S.
AU - Watts, Justin M.
AU - Taylor, Justin
AU - Stone, Richard
AU - Gourineni, Vikram
AU - Marino, Alyssa J.
AU - Yao, Huilan
AU - Destenaves, Benoit
AU - Yuan, Xiaobin
AU - Yu, Kun
AU - Dar, Sara
AU - Ohanjanian, Lernik
AU - Kuida, Keisuke
AU - Xiao, Jianjun
AU - Scholz, Catherine
AU - Gualberto, Antonio
AU - Platzbecker, Uwe
N1 - Funding Information:
This clinical trial was supported by H3 Biomedicine and Eisai. DPS is supported by the Edward P. Evans Foundation, NIH SPORE P50 CA206963, the James & Lois Champy Fund, and the Russell Hartmann Memorial Fund.
Funding Information:
The study protocol was approved by the Institutional Review Boards at each participating center; all patients provided written informed consent prior to any study screening procedures, and the study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice regulations. The study was registered at Clinicaltrials.gov (Identifier NCT02841540) prior to enrollment of the first patient. Study drug was provided by H3 Biomedicine Inc., Cambridge, Massachusetts, USA, which also provided scientific, logistical and financial support for the trial.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1–40 mg, n = 65) and schedule II (21 days on/7 days off, 7–20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.
AB - We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1–40 mg, n = 65) and schedule II (21 days on/7 days off, 7–20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.
UR - http://www.scopus.com/inward/record.url?scp=85108789184&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85108789184&partnerID=8YFLogxK
U2 - 10.1038/s41375-021-01328-9
DO - 10.1038/s41375-021-01328-9
M3 - Article
C2 - 34172893
AN - SCOPUS:85108789184
SN - 0887-6924
VL - 35
SP - 3542
EP - 3550
JO - Leukemia
JF - Leukemia
IS - 12
ER -