PYNNACLE phase 2 clinical trial of rezatapopt in patients with advanced solid tumors harboring a TP53 Y220C mutation.

Abstract

TPS11581 Background: TP53, encoding p53 protein, is one of the most frequently mutated genes across all cancers, with TP53 mutations found in ~59% of all solid tumors. TP53 mutations result in the loss of p53 tumor suppressor functions leading to tumor development and progression. The TP53 Y220C mutation, occurring in ~1% of all solid tumors, is a missense mutation that destabilizes the p53 protein. Rezatapopt (also known as PC14586) is an investigational, first-in-class, selective, p53 reactivator specific to the TP53 Y220C mutation that restores wildtype p53 function. Preliminary findings from Phase 1 part of the PYNNACLE (NCT04585750) Phase 1/2 study, showed that rezatapopt had a favorable safety profile and single-agent efficacy in heavily pre-treated patients with solid tumors harboring a TP53 Y220C mutation (Schram A, AACR-NCI-EORTC 2023, LBA25). Here we describe the study design for the registrational Phase 2 part of the PYNNACLE study. Method(s): The Phase 2 part of PYNNACLE is an ongoing, global, single-arm, open-label, multicenter basket trial in patients with solid tumors harboring a TP53 Y220C mutation (Table). Patients must have measurable disease at baseline, ECOG performance status 0 or 1, and adequate organ function; other key inclusion criteria are listed in the table. Patients with KRAS single nucleotide variants, primary CNS tumors and unstable brain metastases are excluded. Eligible patients receive rezatapopt 2000mg, orally, once daily, taken with food, for continuous 21-day cycles. Patients are followed until death, lost to follow-up, two years after last patient discontinuation, or end of study. As of March 2024, =114 patients are planned to be enrolled. Clinical trial information: NCT04585750. Table Presented.Copyright © 2025 by American Society of Clinical Oncology