Phase I first-in-human dose escalation study of the oral casein kinase 1α and cyclin dependent kinase 7/9 inhibitor BTX A51 in advanced MDS and AML Journal Article

   

Authors:	Ball, B. J.; Xiao, W.; Borthakur, G.; Nguyen, L. X. T.; Valerio, M.; Venkatachalam, A.; Marcucci, G.; Stein, A. S.; Thai, D. L.; Cook, D. N.; Chan, K.; Persaud, S.; Levine, R. L.; Abdel-Wahab, O.; Ben-Neriah, Y.; Stein, E. M.
Article Title:	Phase I first-in-human dose escalation study of the oral casein kinase 1α and cyclin dependent kinase 7/9 inhibitor BTX A51 in advanced MDS and AML
Abstract:	Background: BTX A51, a first-in-class oral small molecule inhibitor of casein kinase 1α (CK1α) and cyclin-dependent kinase (CDK) 7 and 9, induces apoptosis of leukemic cells by activating p53 and inhibiting expression of Mcl1. Here, we report on the results of the phase 1 clinical trial of BTX A51 in patients with relapsed or refractory AML and MDS. Methods: Adult patients with R/R AML and high-risk MDS were enrolled into eight potential doses ranging from 1 to 42 mg dosed orally three days/week for 21 or 28 days out of a 28-day cycle. The maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of BTX A51 were investigated. Results: Thirty-one patients were enrolled and received treatment with BTX A51. Median age was 75 (range 22- 84) and 55% were male. Most patients (97%) had received prior treatment with venetoclax and hypomethylating agents. The most common treatment-emergent adverse events of any grade were nausea (67%), emesis (63%), hypokalemia (53%), and diarrhea (40%). Two patients experienced hepatic toxicity as DLTs, which resolved upon holding treatment. No treatment-related deaths occurred. The recommended phase 2 dose was 21 mg dosed three days/week for 4 weeks of a 28-day cycle. BTX A51 increased the expression of p53 and reduced the expression of MCL1 and RNA polymerase II phosphorylation in pre- and post-treatment immunocytochemistry studies. Overall, 3 patients (10%) experienced complete remission with incomplete count recovery (CRi). All 3 responding patients had RUNX1 mutations and the CR/CRi rate for RUNX1-mutated patients receiving BTX A51 at efficacious doses (11 mg or higher) was 30%. Ex-vivo studies confirmed higher efficacy of BTX A51 on RUNX1-mutated myeloblasts and demonstrated synergy with azacitidine and venetoclax. Conclusions: Although the overall efficacy was modest, this study lays the groundwork for future studies with improved patient selection and combination approaches. Trial registration: NCT04872166. © The Author(s) 2025.
Keywords:	adult; clinical article; controlled study; protein expression; protein phosphorylation; aged; aged, 80 and over; middle aged; unclassified drug; gene mutation; leukemia, myeloid, acute; clinical trial; constipation; fatigue; cancer recurrence; advanced cancer; area under the curve; diarrhea; dose response; drug efficacy; drug potentiation; drug safety; drug withdrawal; hypophosphatemia; patient selection; antineoplastic agents; antineoplastic agent; gene; controlled clinical trial; anemia; cyclin dependent kinase 9; protein kinase inhibitor; nausea; thrombocytopenia; vomiting; drug effect; dose-response relationship, drug; protein p53; high risk patient; alanine aminotransferase blood level; coughing; drug dose escalation; dyspnea; febrile neutropenia; fever; hypomagnesemia; pneumonia; protein kinase inhibitors; hypoxia; alanine aminotransferase; hypokalemia; hyponatremia; hypotension; cancer regression; myelodysplastic syndrome; death; drug mechanism; immunocytochemistry; protein mcl 1; peripheral edema; sepsis; open study; targeted therapy; maximum tolerated dose; phase 1 clinical trial; drug half life; drug therapy; ex vivo study; administration, oral; epistaxis; rna polymerase ii; azacitidine; myelodysplastic syndromes; hypocalcemia; oral drug administration; cyclin-dependent kinase 9; refractory; aml; mds; molecularly targeted therapy; acute respiratory failure; relapsed; acute myeloid leukemia; myeloblast; very elderly; humans; human; male; female; article; casein kinase ialpha; runx1 gene; cdk9 protein, human; venetoclax; maximum concentration; casein kinase 1α; cyclin-dependent kinase 7/9; btx a51
Journal Title:	Journal of Hematology & Oncology
Volume:	18
ISSN:	1756-8722
Publisher:	Biomed Central Ltd
Date Published:	2025-07-15
Start Page:	73
Language:	English
DOI:	10.1186/s13045-025-01724-z
PUBMED:	40665325
PROVIDER:	scopus
PMCID:	PMC12265154
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-105010729453&doi=10.1186%2fs13045-025-01724-z&partnerID=40&md5=3424a0db32db7ee2b3909592073b04b0
Notes:	Article -- MSK corresponding author is Eytan Stein -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/227285