Journal: The New England journal of medicine
Study type and population
- Phase 1, single‑arm, dose‑escalation and dose‑optimization trial of rezatapopt, an oral, selective p53 reactivator targeting TP53 Y220C.
- 77 heavily pretreated patients with locally advanced or metastatic solid tumors harboring TP53 Y220C were enrolled.
Treatment and dosing
- Doses explored: 150–2500 mg once daily and 1500 mg twice daily, given in continuous 21‑day cycles.
- Maximum tolerated dose: 1500 mg twice daily.
- Recommended phase 2 dose (RP2D): 2000 mg once daily with food, based on integrated safety, efficacy, and pharmacokinetic data.
Safety
- Overall AEs: 99% of patients experienced at least one adverse event (AE); 38% had only grade 1–2 AEs.
- Most common AEs: nausea (58%), vomiting (44%), increased creatinine (39%), fatigue (39%), anemia (36%).
- Treatment‑related AEs: occurred in 87% of patients; mostly grade 1–2 (62%).
- Discontinuations: 3% discontinued due to treatment‑related AEs.
- ≥grade 3 AE: anemia was the most common (16%).
- GI AEs: largely manageable symptomatically and were less frequent when taken with food.
Efficacy
- Overall response rate (ORR) (confirmed complete or partial responses) was 20% across all patients.
- Wild‑type tumor subgroup: among patients with “wild‑type tumor” who received ≥1150 mg once daily, ORR was 30%.
- Tumor types with confirmed responses: included ovarian and breast cancers.
- Responders: all had solid tumors harboring TP53 Y220C, with wild‑type status for the other gene noted in the abstract.
Key takeaway for practice/research
- Rezatapopt shows manageable toxicity dominated by GI effects and anemia, and demonstrates antitumor activity across several TP53 Y220C‑mutated solid tumors, providing clinical proof‑of‑concept for mutation‑specific p53 reactivation and supporting further phase 2 evaluation at 2000 mg once daily with food.