Eprenetapopt combined with venetoclax and azacitidine in TP53-mutated acute myeloid leukaemia: a phase 1, dose-finding and expansion study

by Selleckchem | Jun 24 2023

Background: TP53-mutated acute myeloid leukaemia is associated with poor outcomes. Eprenetapopt (APR-246) is a first-in-class, small-molecule p53 reactivator. We aimed to evaluate the combination of eprenetapopt and venetoclax with or without azacitidine in patients with TP53-mutated acute myeloid leukaemia.

Methods: This phase 1, multicentre, open-label, dose-finding and cohort expansion study was done at eight academic research hospitals in the USA. Inclusion criteria were age of at least 18 years; at least one pathogenic TP53 mutation; treatment-naive acute myeloid leukaemia according to the 2016 WHO classification; an ECOG performance status of 0-2; and a life expectancy of at least 12 weeks. In dose-finding cohort 1 patients received previous therapy with hypomethylating agents for myelodysplastic syndromes. In dose-finding cohort 2, previous use of hypomethylating agents was not permitted. Treatment cycles were 28 days. Patients in cohort 1 received intravenous eprenetapopt 4·5 g/day on days 1-4 and oral venetoclax 400 mg/day on days 1-28; those in cohort 2 also received subcutaneous or intravenous azacitidine 75 mg/m2 on days 1-7. The expansion part of the study proceeded with patients enrolled as in cohort 2. Primary endpoints were safety in all cohorts (assessed in patients receiving at least one dose of assigned treatment) and complete response in the expansion cohort (assessed in patients who completed at least one treatment cycle and had at least one post-treatment clinical response assessment). The trial is registered with ClinicalTrials.gov, NCT04214860, and is complete.

Findings: Between Jan 3, 2020, and July 22, 2021, 49 patients were enrolled across all cohorts. Six patients were initially enrolled into each of dose-finding cohorts 1 and 2; after no dose-limiting toxicities were observed, cohort 2 was expanded to enrol an additional 37 patients. The median age was 67 years (IQR 59-73). 24 (49%) of 49 patients were female and 25 (51%) male, and 40 (82%) were White. At data cutoff (Oct 1, 2021), the median length of follow-up was 9·5 months (IQR 6·1-11·5). No dose-limiting toxicities were recorded and the recommended phase 2 dose for eprenetapopt combinations was 4·5 g/day on days 1-4. Across all patients, adverse events of grade 3 or worse occurring in at least 20% of patients were febrile neutropenia (23 [47%] of 49 patients), thrombocytopenia (18 [37%] patients), leukopenia (12 [25%] patients), and anaemia (11 [22%] patients). Treatment-related serious adverse events occurred in 13 (27%) of 49 patients and there was one (2%) treatment-related death (sepsis). 25 (64%, 95% CI 47-79) of 39 patients had an overall response with eprenetapopt and venetoclax with azacytidine; 15 (38%, 23-55) had a complete response.

Interpretation: Eprenetapopt and venetoclax with azacitidine had an acceptable safety profile and encouraging activity, supporting further frontline evaluation of this combination in the treatment of TP53-mutated acute myeloid leukaemia.

Comments:

The study you mentioned is a phase 1 clinical trial that aimed to evaluate the combination of eprenetapopt (APR-246) and venetoclax with or without azacitidine in patients with TP53-mutated acute myeloid leukemia (AML). TP53 mutations are associated with poor outcomes in AML, and eprenetapopt is a small-molecule p53 reactivator, which means it has the potential to restore the function of the p53 tumor suppressor protein.

The study was conducted at eight academic research hospitals in the USA and included patients who were at least 18 years old, had at least one pathogenic TP53 mutation, were treatment-naive for AML according to the 2016 WHO classification, had an ECOG performance status of 0-2, and had a life expectancy of at least 12 weeks. The trial consisted of dose-finding cohorts and a cohort expansion.

In the dose-finding cohorts, patients in cohort 1 had previously received therapy with hypomethylating agents for myelodysplastic syndromes, while patients in cohort 2 were not allowed previous use of hypomethylating agents. Treatment cycles were 28 days long. Patients in cohort 1 received intravenous eprenetapopt (4.5 g/day on days 1-4) and oral venetoclax (400 mg/day on days 1-28). Patients in cohort 2 received eprenetapopt and venetoclax as in cohort 1, but they also received subcutaneous or intravenous azacitidine (75 mg/m2 on days 1-7). The expansion part of the study proceeded with patients enrolled as in cohort 2.

The primary endpoints of the study were safety in all cohorts and complete response in the expansion cohort. Safety was assessed in patients who received at least one dose of the assigned treatment, while complete response was assessed in patients who completed at least one treatment cycle and had at least one post-treatment clinical response assessment.

A total of 49 patients were enrolled in the study between January 3, 2020, and July 22, 2021. Six patients were initially enrolled in each of the dose-finding cohorts, and after no dose-limiting toxicities were observed, cohort 2 was expanded to include an additional 37 patients. The median age of the patients was 67 years, and the majority of patients were White. At the data cutoff (October 1, 2021), the median length of follow-up was 9.5 months.

No dose-limiting toxicities were recorded, and the recommended phase 2 dose for eprenetapopt combinations was determined to be 4.5 g/day on days 1-4. Adverse events of grade 3 or worse that occurred in at least 20% of patients included febrile neutropenia, thrombocytopenia, leukopenia, and anemia. Treatment-related serious adverse events occurred in 27% of patients, and there was one treatment-related death due to sepsis.

In terms of efficacy, 64% of the patients in the expansion cohort had an overall response to the treatment with eprenetapopt and venetoclax with azacitidine. Additionally, 38% of the patients had a complete response.

Based on these findings, the study concluded that the combination of eprenetapopt and venetoclax with azacitidine had an acceptable safety profile and showed encouraging activity in patients with TP53-mutated AML. These results support further evaluation of this combination as a frontline treatment for TP53-mutated AML.