Acute myeloid leukemia (AML) cells in blood flow: © LASZLO – stock.adobe.com
Results from a phase 1 first-in-human dose-escalation study (NCT04872166) evaluating BTX A51 revealed the agent’s tolerability with manageable adverse events, alongside suppressed MCL1 expression in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS).1,2
Brian J. Ball, MD, and colleagues wrote in the study1 that “10% (3 of 31) patients experienced a complete remission with incomplete count recovery (CRi). Specifically, these 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%.” The median duration of response was 1.9 months (range 1.5-2.5), though all 3 responding patients discontinued treatment after relapse.
Thirty-one patients were enrolled between January 13, 2025 through February 28, 2022, to receive oral doses of BTX A51 ranging from 1 mg to 42 mg 3 days a week. Dosing schedules varied: 1 mg was given 5 days per week for 21 days over a 28-day cycle; 3 mg, 5 mg, 8 mg, 11 mg, 21 mg, and 42 mg doses were administered 3 days per week for 21 days over a 28-day cycle; and a 21 mg dose was also explored 3 days per week for 28 days over a 28-day cycle. Patients remained on treatment for a median of 24 days, with a range of 3 to 135 days.
The primary end points were safety, maximum tolerated dose, and recommended phase 2 dose based on the incidence of dose-limiting toxicities (DLTs) during cycle 1. Secondary end points included estimated preliminary efficacy, overall and event-free survival, pharmacokinetics, and pharmacodynamics.
Of the 31 patients, 28 had R/R AML and 3 patients had high-risk R/R MDS. The median age was 75 years (range, 22–84) and the median number of prior lines of therapy was 2 (range, 1-8). Overall, 97% had received prior venetoclax (Venclaxta) and hypomethylating agents and 43% exhibited no response after 2 lines of induction chemotherapy.
The majority (55%) of patients were male, 3 patients had prior allogeneic hematopoietic cell transplantation, and 12 (38%) harbored RUNX-1–mutated tumors.
Overall safety showed that all patients had at least 1 treatment-emergent adverse event (TEAE) of any grade with the most common occurring in 10% or more patients were nausea (67%), emesis (63%), hypokalemia (53%), and diarrhea (40%). Reported TEAEs of grade 3 or higher were febrile neutropenia (33%), anemia (33%), thrombocytopenia, and hypokalemia (23% each).
Investigators determined that 1 patient experienced a DLT during cycle 1 and 1 patient developed a grade 3 elevation in alkaline phosphatase level at the 21 mg dose that resolved 4 days after holding treatment. Another patient experienced encephalopathy and grade 3 hepatic failure with elevations in aspartate aminotransferase, alanine transaminase, and bilirubin, resulting in discontinuation of the 42 mg dose.
Overall, there were 11 deaths among patients during the study treatment and within 28 days of the last dose. Five of these deaths were attributed to disease progression. Six deaths occurred in the absence of overt disease progression due to lung infection, cardiac arrest, intracranial hemorrhage, fungal infection, and septic shock.
The investigators also performed in-vitro and ex-vivo studies on AML cell lines and primary patient samples to evaluated antileukemic activity in patients with RUNX1 mutant and wild type. They observed a decrease in the expression of oncogenes such as MYC and MDM2.
“Importantly, this oncogene suppression, accompanied by the downregulation of the anti-apoptotic protein MCL1, led to the activation of p53 or DNA damage response and subsequent cleavage of caspase 3, thereby inducing leukemia cell apoptosis,” the investigators wrote in their paper.
These findings were modest but encouraging and the next steps will be exploring the agent in combination with azacitidine and with azacitidine and venetoclax (Venclexta).