BTX A51, an oral casein kinase 1α and cyclin dependent kinase 7/9 inhibitor, has shown notable tolerability and manageable safety in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). In a phase 1 first-in-human dose-escalation study, the agent demonstrated promising results with a focus on safety and tolerability. The study, conducted between January 13, 2025, and February 28, 2022, included 31 patients receiving varying oral doses of BTX A51, ranging from 1 mg to 42 mg, administered 3 days a week. Dosing schedules were diverse, with different doses and frequencies explored over a 28-day cycle. Patients remained on treatment for a median of 24 days, showcasing the feasibility and potential efficacy of BTX A51 in this patient population.
The primary objectives of the study were to assess safety, determine the maximum tolerated dose, and establish the recommended phase 2 dose based on the occurrence of dose-limiting toxicities during the initial cycle. Secondary endpoints included evaluating preliminary efficacy, overall and event-free survival, pharmacokinetics, and pharmacodynamics.
The results indicated that BTX A51 exhibited a manageable safety profile, with minimal adverse events and notable outcomes in patients with R/R AML or MDS.
Among the key findings of the study, 10% of patients experienced a complete remission with incomplete count recovery (CRi), particularly those with RUNX1 mutations. The CR/CRi rate for RUNX1-mutated patients receiving BTX A51 at efficacious doses (11 mg or higher) was 30%. While the median duration of response was 1.9 months, all responding patients discontinued treatment after relapse, highlighting the need for further research and optimization of treatment strategies.
In terms of safety, all patients experienced at least one treatment-emergent adverse event (TEAE), with common events including nausea, emesis, hypokalemia, and diarrhea. Grade 3 or higher TEAEs such as febrile neutropenia, anemia, thrombocytopenia, and hypokalemia were reported in a subset of patients. Overall, the safety profile of BTX A51 was deemed acceptable, with manageable adverse events and a focus on improving patient outcomes.
This study underscores the potential of BTX A51 as a promising therapeutic option for patients with R/R AML or MDS, warranting further investigation and clinical development to optimize its efficacy and safety in this challenging patient population.
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