Phase 1/2 Trial of Frontline Eprenetapopt Plus Venetoclax and Azacitidine for TP53-Mutant AML Meets End Point

A trial of an eprenetapopt combination has met the prespecified primary efficacy end point in patients with acute myeloid leukemia harboring TP53 mutations.

Treatment with eprenetapopt plus venetoclax (Venclexta) and azacitidine in patients with TP53-mutant acute myeloid leukemia (AML) has met the prespecified primary complete remission (CR) rate end point in a phase 1/2 trial, according to the agent’s developer, Aprea Therapeutics, Inc.1

This study evaluated 30 patients for efficacy and found that the CR rate was 37%. The composite response rate of CR plus CR with incomplete hematologic recovery (CRI) was 53%. At the time of the data cut, 11 patients remained on the treatment and will be evaluated for safety and efficacy.

“We are pleased with these results from the combination of eprenetapopt with venetoclax and azacitidine in this very difficult-to-treat TP53-mutant AML population, a patient group with significant unmet medical need,” Eyal Attar, MD, Chief Medical Officer of Aprea Therapeutics, said in a press release. “These data, which follow the recent granting of Fast Track and Orphan Drug designations by FDA, provide further demonstration of the potential for eprenetapopt in the treatment of myeloid malignancies,” said Attar.

A previously reported clinical trial of eprenetapopt plus azacitidine showed that it was well tolerated with a high response rate. Investigators looked at 55 patients with the TP53 mutations that included 40 with myelodysplastic syndrome (MDS), 11 with AML, and 4 with MDS/myeloproliferative neoplasms.

The primary end point for the study was CR, with secondary end points being overall response rate (ORR), duration of response, and overall survival (OS). The ORR was 71% including the 44% who achieved CR. Twenty-nine patients with MDS responded (73%), of whom 20 achieved CR (50%) and 23 had a cytogenetic response (58%). For patients with AML, 7 responded (64%) and 4 achieved CR (36%). Those patients with no other mutations detected by next-generation sequencing had higher rates of CR (69% vs 25%; P = .006).2

Patients with a response had a reduction in TP53 variant allele frequency, with 38% achieving complete molecular remission.

The median overall survival was 10.8 months, with those receiving at least 4 cycles of treatment achieving the best results (P = .01). Those patients who responded had a median OS that was longer at 14.6 months versus nonresponding patients at 7.5 months.

Some common adverse effects of treatment were dizziness (36%), peripheral sensory neuropathy (31%), ataxia (24%), and tremors (20%). These were seen in less than 20% of patients and were most common during the infusion phase and resolved quickly. The mortality rate was very low with only one death within 30 days of the trial.

Investigators found that those patients who experienced a deepening of cytogenic and molecular responses should have a longer duration of azacitidine and eperenetapopt prior to hematopoietic stem cell transplantation. This is important to prevent a risk of relapse.


1. Aprea Theraputics Announces Phase 1/2 Trial of Eprenetapopt + Venetoclax + Azacitidine in TP53 Mutant AML Meets Complete Remission Primary Efficacy Endpoint. News Release. Aprea Therapeutics, Inc. June 16, 2021. Accessed June 17, 2021.

2. Sallman DA, DeZern AE, Garcia-Manero G, et al. Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes. J Clin Oncol. 2021;39(14):1584-1594. doi:10.1200/JCO.20.02341