Eprenetapopt (APR-246), Aprea Therapeutics’ lead cancer therapy candidate, was well-tolerated and showed promising clinical activity when given alongside azacitidine to treat patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) with mutations in the tumor suppressor TP53 gene.
According to the company, findings from this Phase 1b/2 trial (NCT03072043) support the continuation of a Phase 3 trial (NCT03745716) that is currently assessing the safety and efficacy of the combination therapy in patients with MDS and TP53 mutations.
“The data is promising and supports the current phase 3, multicenter trial, which we hope will lead to FDA approval and a new much-needed treatment option for this patient population,” David Sallman, MD, principal investigator of the trial and the study’s first author, said in a press release.
Findings from this Phase 1b/2 trial were reported in the study, “Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes,” published in the Journal of Clinical Oncology.
Both MDS and AML are rare blood cancers that can arise spontaneously or as a result of treatments for other types of malignancies. These types of cancers usually are associated with mutations in TP53, a gene that provides instructions for making the p53 tumor suppressor protein that is responsible for controlling cell proliferation.
Standard treatments for these blood malignancies usually consist of administering hypomethylating agents, like azacitidine (sold as Vidaza and Onureg) or decitabine (sold as Dacogen). These chemotherapy medications kill cells, such as cancer cells, that divide too quickly. However, in patients with TP53 mutations, clinical remission driven by these therapies is usually short-lived and patient clinical outcomes, particularly survival, tend to be poor.
“Patients with TP53-mutant disease, which is roughly 10% to 20% of AML and de novo MDS cases, don’t have many options for therapy with nondurable responses to standard therapy. There is clearly a need for new targeted therapies for this patient population,” said Sallman, also an assistant member of the malignant hematology department at the Moffitt Cancer Center, in Florida.
Eprenetapopt is a first-in-class, small molecule that is designed to promote the reactivation of the mutant and inactivated form of the p53 tumor suppressor protein, thereby promoting the destruction of cancer cells harboring TP53 mutations.
Data from previous preclinical and clinical studies showed eprenetapopt had promising anti-cancer clinical activity in both solid and liquid tumors, including AML and MDS. The experimental therapy also has been found to work well and boost the effectiveness of standard anti-cancer therapies, including azacitidine.
Sallman and his colleagues are conducting the Phase 1b/2 trial to explore the therapeutic potential of a combination of eprenetapopt and azacitidine in patients with AML and MDS who have TP53 mutations.
The trial was divided into two parts. The initial dose-escalation part aimed to determine eprenetapopt’s recommended dose, to be used in the study’s second, expansion phase. That second phase was designed to assess the therapy’s safety and efficacy at prolonging patients’ overall survival.
A total of 55 participants — 40 with MDS, 11 with AML, and four with MDS or myeloproliferative neoplasms — with at least one TP53 mutation received the combination therapy.
Among the overall patient population, 71% responded to treatment, and nearly half (44%) attained a complete response, or full cancer elimination, according to data gathered until Nov. 15, 2019. These values were slightly lower in the subset of patients with AML, 64% of whom responded to treatment and 36% of whom attained a complete response.
Patients treated with the combination therapy lived for a median of 10.8 months, with those responding to treatment living significantly longer than those who failed to respond to the combination therapy. Specifically, the median overall survival was 14.6 months versus 7.5 months.
Moreover, around a third (35%) of the patients who were treated with the combination therapy were able to move ahead and receive a stem cell transplant, achieving a median overall survival of 14.7 months.
The combination therapy also was found to have a favorable safety profile that was consistent with that of each of the two therapies when given separately. The most common severe side effects were low neutrophil (a type of white blood cell) counts accompanied by fever (33%), low white blood cell counts (29%), and low neutrophil counts (29%).
“In conclusion, eprenetapopt in combination with azacitidine is well-tolerated and yields high remission rates in patients with TP53-mutant MDS and AML,” the researchers wrote.
They also noted these findings are in agreement with those recently reported in another Phase 1/2 trial (NCT03588078), and support the continuation of a Phase 3 trial that is currently assessing the safety and efficacy of the same combination therapy in MDS patients with TP53 mutations.
Eprenetapopt has received fast track designation by the U.S. Food and Drug Administration for treating AML with mutations in the TP53 gene. That designation is intended to accelerate the therapy’s development and expedite its approval by providing more frequent meetings with the FDA and discussions about the development plan.
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