Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms
| Autor: | David P. Steensma, Lionel Ades, Ian W. Flinn, Rami S. Komrokji, Jaime Pérez de Oteyza, Peter L. Greenberg, Keisuke Kuida, Hetty E. Carraway, Huilan Yao, Antonio Gualberto, James M. Foran, Catherine C. Coombs, Benoit Destenaves, Ana Alfonso-Piérola, Xiaobin Yuan, Patricia Font, Jianjun Xiao, Andrew M. Brunner, Kun Yu, Eunice S. Wang, Catherine Scholz, Uwe Platzbecker, Michael B. Maris, Jay Yang, Malgorzata McMasters, Alyssa J. Marino, Guillermo Garcia-Manero, Jean Baptiste Micol, Juan M. Alonso-Dominguez, Martin Wermke, Sara Dar, H. Joachim Deeg, Felicitas Thol, Virginia M. Klimek, Richard Stone, Justin M. Watts, Vikram Gourineni, Justin Taylor, Lernik Ohanjanian, Aref Al-Kali |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Myeloid Pyridines Nausea Mutation Missense Administration Oral Phases of clinical research Drug development Gastroenterology Piperazines Article Medical research hemic and lymphatic diseases Internal medicine Biomarkers Tumor medicine Humans Dosing Adverse effect Aged Aged 80 and over Hematology Dose-Response Relationship Drug business.industry Health sciences Middle Aged Phosphoproteins Leukemia Myeloid Acute Red blood cell Treatment Outcome medicine.anatomical_structure Oncology Myelodysplastic Syndromes Vomiting Female Patient Safety RNA Splicing Factors medicine.symptom business |
| Zdroj: | Leukemia |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/s41375-021-01328-9 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink