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Abstract Background: 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. To minimize potential thrombocytopenia previously seen with antagonism of this target, ASTX295 was designed to have a short half-life (t1/2) with decreased bone marrow (BM) exposure. ASTX295 has proapoptotic and tumor growth inhibitory activity in preclinical cancer (CA) models. We report here the safety and preliminary efficacy of the phase 1 and dose expansion portions of Study ASTX295-01. Methods: ASTX295-01 is a first-in-human, open-label, multicenter, phase 1/2 study to assess safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of ASTX295 (NCT03975387). Eligible patients (advanced solid tumors with Wild-Type WT TP53, ECOG PS 0-2, adequate organ and bone marrow function, etc. ) had oral administration of ASTX295 starting at a daily dose of 15 mg. Dose escalation was by standard 3 + 3 with cohorts testing multiple regimens. Safety was assessed by CTCAE and disease was assessed by RECIST 1. 1. Safety and efficacy and dosing recommendations were overseen by the Data Safety Review Committee. Results: 83 subjects were enrolled in over 14 cohorts, evaluating daily (QD) and intermittent dosing regimens and the effect of food. The mean age of subjects on study was 60. 1 year, 56. 9 were male, with 2. 94 (0-15) prior chemotherapy regimens. For PK exposure, the total weekly AUC for 400 mg QD and 660 twice a week (BIW) are similar. The median tmax is 3 hours and mean t1/2 is 4-6 hours. PD demonstrates p53 pathway modulation. Nausea, vomiting, diarrhea, and fatigue were dose limiting. RP2D regimens were 660 mg BIW and 400 mg QD and these regimens were expanded with a total of 25 additional subjects. The most common treatment related AEs for both regimens were nausea, diarrhea, and vomiting at 76. 2%, 76. 2%, and 33. 3% respectively, for daily and 71. 4%, 47. 6%, and 33. 3%, for intermittent. Grade 3 GI AEs were reported in 14. 3% of subjects in the daily cohort vs 9. 5% in the intermittent; none had Grade ≥ 4. One subject had grade 2 thrombocytopenia. Based on decreased incidence and duration of GI AEs, 660 mg BIW was selected as the RP2D. Multiple objective responses were seen, including 1 subject with non-small cell lung CA and 3 subjects with liposarcoma (LPS), a tumor with frequent MDM2 amplification. For LPS the ORR is 7. 9% (de-differentiated 7. 7%, well differentiated 8. 0%), with a PFS of 7. 95 and 9. 66 months respectively, along with a 16-week disease control rate of 69. 2% and 72. 0%. Five subjects with GBM were enrolled, 4 with MDM2 amplification, 3 of whom showed evidence of tumor regression, with one subject remaining on study for 34 cycles. 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. Citation Format: Ecaterina E. Dumbrava, Fabio M. Iwamoto, Mark Agulnik, Mohammed Milhem, Anthony W. Tolcher, Rashmi Chugh, Michael J. Demeure, Alain Mita, Kurt Demel, Mark Diamond, Beloo Mirakhur, Laksmi Wilson, Aram Oganesian, Danna Chan, Harold N. Keer, Jason Taylor, Martin J. Sims, Andrea Biondo, Simone Jueliger, Alexander Spira. Phase 1 study of MDM2 antagonist ASTX295 in patients with solid tumors with wild-type TP53 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr CT066.
Dumbrava et al. (Fri,) studied this question.