TY - JOUR
T1 - 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
AU - Ball, Brian J.
AU - Xiao, Wenbin
AU - Borthakur, Gautam
AU - Nguyen, Le Xuan Truong
AU - Valerio, Melissa
AU - Venkatachalam, Avanthika
AU - Marcucci, Guido
AU - Stein, Anthony S.
AU - Thai, Dung Luong
AU - Cook, David N.
AU - Chan, Kyle
AU - Persaud, Sonali
AU - Levine, Ross L.
AU - Abdel-Wahab, Omar
AU - Ben-Neriah, Yinon
AU - Stein, Eytan M.
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - 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.
AB - 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.
KW - AML
KW - Casein kinase 1α
KW - Cyclin-dependent kinase 7/9
KW - MDS
KW - Refractory
KW - Relapsed
KW - Targeted therapy
UR - https://www.scopus.com/pages/publications/105010729453
U2 - 10.1186/s13045-025-01724-z
DO - 10.1186/s13045-025-01724-z
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C2 - 40665325
AN - SCOPUS:105010729453
SN - 1756-8722
VL - 18
JO - Journal of Hematology and Oncology
JF - Journal of Hematology and Oncology
IS - 1
M1 - 73
ER -