A first-in-human phase I dose-escalation study of BTX A51, an oral multi-kinase inhibitor targeting casein kinase 1α (CK1α) and cyclin-dependent kinases 7 and 9 (CDK7/9), has demonstrated tolerability and encouraging antileukemic activity in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
The study, conducted at three major cancer centers between January 2020 and February 2022, enrolled 31 patients with heavily pretreated disease. Among the cohort, 28 patients had R/R AML and 3 had high-risk R/R MDS, with a median age of 75 years and a median of 2 prior lines of therapy. Notably, 97% of patients had previously received venetoclax and hypomethylating agents, while 43% had experienced primary induction failure after two lines of chemotherapy.
Treatment Response and Efficacy
The study achieved its primary endpoint of establishing safety and determining the recommended phase 2 dose. Three patients (10%) attained complete remission with incomplete count recovery (CRi), with responses observed at doses of 11 mg and 21 mg administered 3 days per week. The median duration of response was 1.9 months (range 1.5-2.5 months), though all responding patients eventually discontinued treatment after relapse.
Particularly noteworthy was the enriched activity observed in patients harboring RUNX1 mutations. All three responders had RUNX1 mutations, and among the 13 patients with RUNX1-mutated tumors, the overall response rate was 23%. For patients with RUNX1 mutations receiving efficacious doses of 11 mg or higher, the response rate increased to 30%.
"RUNX1 mutations occurred in all four patients with at least 50% bone marrow blast count reduction and all three responders," the investigators reported. This finding is significant given that RUNX1 mutations occur in 10-15% of AML patients and are associated with inferior prognosis after standard treatments.
Safety Profile and Dose Determination
BTX A51 was administered across dose levels ranging from 1 mg to 42 mg using various schedules. The study established 21 mg administered 3 days per week for 28 days over a 28-day cycle as the maximum tolerated dose and recommended phase 2 dose.
All patients experienced at least one treatment-emergent adverse event, with the most common being nausea (67%), emesis (63%), hypokalemia (53%), and diarrhea (40%). Grade 3 or higher adverse events included febrile neutropenia (33%), anemia (33%), thrombocytopenia (23%), and hypokalemia (23%).
Two patients experienced dose-limiting toxicities during cycle 1. One patient developed grade 3 alkaline phosphatase elevation at the 21 mg dose that resolved within 4 days after treatment interruption. Another patient experienced encephalopathy and grade 3 hepatic failure at the 42 mg dose, leading to discontinuation of that dose level despite not meeting formal maximum tolerated dose criteria.
Mechanism of Action and Biomarker Studies
BTX A51's unique mechanism involves simultaneous inhibition of CK1α, which negatively regulates p53, and CDK7/9, which are essential for transcriptional initiation and elongation. This dual targeting approach aims to stabilize p53 while suppressing oncogene expression, particularly at super-enhancer regions.
Pharmacodynamic studies confirmed target engagement, showing increased serum macrophage inhibitory cytokine-1 (MIC-1) levels, a biomarker of p53 activation. Immunocytochemistry studies of CD34+ bone marrow cells from treated patients demonstrated reduced MCL1 expression, decreased RNA polymerase II phosphorylation, and increased p53 and histone H2AX phosphorylation, indicating DNA damage response activation.
Combination Therapy Potential
Ex vivo studies using primary patient samples revealed promising synergistic effects when BTX A51 was combined with venetoclax and azacitidine. RUNX1-mutated CD34+ primary AML blasts showed greater sensitivity to BTX A51 (IC50 17 nM) compared to venetoclax (IC50 82 nM) in co-culture systems.
The combination studies demonstrated that BTX A51 with venetoclax achieved maximal inhibitory effects, while the addition of azacitidine allowed for reduced concentrations of both BTX A51 and venetoclax to achieve similar activity. These findings provide strong rationale for future combination trials.
Clinical Implications
The results are particularly encouraging given the challenging patient population, with nearly all patients having failed prior venetoclax-based therapy. For patients with R/R AML after venetoclax failure, median overall survival is typically only 2.4 months, highlighting the urgent need for new therapeutic approaches.
The enriched activity in RUNX1-mutated patients is especially significant, as this subset currently lacks targeted therapeutic options despite their poor prognosis with standard treatments. The investigators noted that "the increased responses and anti-leukemic activity of BTX A51 in RUNX1-mutated patients are encouraging, and additional clinical trials evaluating BTX A51 as a possible RUNX1 targeting therapy as monotherapy and in combination are warranted."
Future Development
Based on these promising results, the next phase of clinical development will explore BTX A51 in combination with azacitidine and with azacitidine plus venetoclax. The established safety profile at the recommended phase 2 dose of 21 mg, combined with the mechanistic rationale for combination therapy and encouraging single-agent activity, particularly in RUNX1-mutated patients, supports continued development of this novel therapeutic approach for patients with limited treatment options.
