FDA Grants Breakthrough Designation to APR-246/Azacitidine Combo in TP53-Mutant MDS

The FDA has granted a breakthrough therapy designation to the combination of APR-246 and azacitidine for the treatment of patients with myelodysplastic syndromes (MDS) with a susceptible TP53 mutation.¹

“Breakthrough therapy designation further supports our development program for APR-246 in combination with azacitidine in MDS patients with a TP53 mutation,” Christian S. Schade, chief executive officer of Aprea Therapeutics, the developer of APR-246, stated in a press release. “Outcomes for MDS patients with a TP53 mutation are poor and there are no current therapeutic options specifically for these patients. We look forward to continued interaction with FDA regarding our ongoing phase III clinical study and our clinical development program to advance APR-246.”

Approximately 30% to 40% of patients with MDS progress to acute myeloid leukemia (AML), and the presence of the mutation of the p53 tumor suppressor protein is believed to be a direct association with disease progression and a poor prognosis.

APR-246 is a small molecule with demonstrated reactivation of mutant and inactivated p53 protein, by restoring wild-type p53 conformation and function, and inducing programmed cell death in cancer cells, Aprea Therapeutics stated in the press release.

Preclinical activity has been reported with APR-246 in MDS, AML, and ovarian cancer, among other malignancies, and the agent has also shown synergy with chemotherapy and other classes of agents. In a phase I/II clinical program, APR-246 was found to demonstrate clinical activity and a favorable safety profile in TP53-mutant hematological malignancies and solid tumors.

A small, phase Ib trial previously examined this combination in hypomethylating agents—naïve patients with TP53-mutant MDS and oligoblastic AML.² Intravenous (IV) APR-246 was given daily in a 3+3 dose-escalation design—50 mg/kg, 75 mg/kg, or 100 mg/kg—in a lead-in phase followed by the same dose combined with azacitidine at 75 mg/m² subcutaneously or IV over 7 days in 28-day cycles.

The primary endpoint was safety; secondary endpoints included response by International Working Group (IWG) 2006 criteria, serial next-generation sequencing (NGS), and p53 immunohistochemistry (IHC) for evaluation of clonal suppression and remission depth.

All patients were ≥18 years old. As of January 1, 2017, 9 patients enrolled and 3 patients were in each cohort. Thirty-three percent of patients were male, and the median age was 65 years old (range, 39-73). AML with myelodysplasia-related changes was present in 3 patients, and 6 patients had MDS. All patients had poor-risk cytogenetics and higher-risk disease, as determined by the Revised International Prognostic Scoring System, and the median bone marrow blasts were 18%.

Five patients were evaluable for response. Results showed that the objective response rate by IWG was 100%, with 4 complete responses (CRs) and 1 marrow CR. All patients who had CR achieved complete cytogenetic response. Additionally, 1 patient in CR achieved a marrow CR (MCR) and partial cytogenetic response following APR-246 lead-in prior to combination therapy. All patients in CR had high p53 positivity by IHC at baseline, and serial NGS with a variant allele frequency cutoff of 2% was negative in 80% of patients. The maximum-tolerated dose had not been reached.

Seven patients (78%) remain on study, and 2 patients receiving the combination at the 50-mg/kg APR-246 cohort discontinued treatment. One of the patients discontinued treatment due to an infection that occurred in cycle 2 and later died of sepsis, which was not treatment-related. The other patient discontinued in durable MCR following 5 cycles of treatment.

The median time on study was 106 days (range, 14-221). Treatment-related adverse events (AEs) during the lead-in phase were all grade 1 and included ataxia (n = 1), dizziness (n = 1), and facial numbness (n = 1). AEs that occurred in >1 patient, most of which were grades 1/2, included dizziness (n = 3), nausea (n = 3), neutropenia (n = 3), thrombocytopenia (n = 3), infection (n = 3), headache (n = 2), pain (n = 2), weakness (n = 2), falls (n = 2), facial numbness (n = 2), and ataxia (n = 2). Grade 4 AEs included neutropenia and thrombocytopenia, and no treatment-related serious AEs or dose-limiting toxicities had occurred.

An ongoing pivotal phase III trial (NCT03745716) will evaluate APR-246 and azacitidine as a frontline treatment for patients with TP53-mutant MDS.

Aprea stated that APR-246 previously received orphan drug status as well as fast track designation from the FDA for patients with MDS. Additionally, the European Medicines Agency granted an orphan drug designation to the agent for patients who have MDS, AML, or ovarian cancer.

References

1. Aprea Therapeutics Receives FDA Breakthrough Therapy Designation for APR-246 in Combination with Azacitidine for the Treatment of Myelodysplastic Syndromes (MDS) with a TP53 Mutation [news release]: Boston, MA. Aprea Therapeutics, Inc. Published January 30, 2020. https://bit.ly/36I5gi9. Accessed January 30, 2020.
2. Sallman DA, DeZern A, Sweet K, et al. Phase Ib/II combination study of APR-246 and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Clin Can Res. 2018;78(suppl 13; abstr CT068). doi: 10.1158/1538-7445.AM2018-CT068.