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 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
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
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 -