Phase 1 study of MDM2 antagonist ASTX295 in patients with solid tumors with wild-type TP53

ASTX295 is a novel small molecule antagonist of human Murine Double Minute 2 (MDM2), which tightly regulates the level and activity of the p53 tumor suppressor. According to the data presented at the AACR 2024 conference, the study enrolled 83 participants across 14 cohorts, investigating various dosing regimens and the impact of food intake. The pharmacokinetic analysis revealed similar total weekly exposure for 400 mg once daily and 660 mg twice weekly, with a median time to maximum concentration of 3 hours and a mean half-life of 4-6 hours. Moreover, the pharmacodynamic assessments showed modulation of the p53 pathway. Nausea, vomiting, diarrhea, and fatigue were identified as dose-limiting toxicities. The recommended Phase II dosing (RP2D) regimens were determined as 660 mg twice weekly and 400 mg once daily, with an additional 25 subjects enrolled for further evaluation. 

The most common treatment-related adverse events were nausea, diarrhea, and vomiting. Grade 3 gastrointestinal adverse events were reported in 14.3% of subjects on the daily regimen and 9.5% on the intermittent regimen, with no Grade ≥ 4 events. The 660 mg twice-weekly regimen was selected as the RP2D due to decreased incidence and duration of gastrointestinal adverse events. ORR was observed, including in subjects with non-small cell lung cancer and liposarcoma, a tumor often associated with MDM2 amplification. For liposarcoma, the overall response rate was 7.9%, with promising progression-free survival and disease control rates. Additionally, positive outcomes were noted in subjects with glioblastoma, particularly those with MDM2 amplification, with evidence of tumor regression and prolonged study participation.

Conclusion

ASTX295 was well tolerated at doses producing p53 pathway modulation with manageable toxicities, notably avoiding significant thrombocytopenia. Preliminary single-agent efficacy was observed in heavily pretreated subjects across multiple solid tumor types with WT TP53.