Rezatapopt, a novel oral drug designed to reactivate the p53 protein in tumors harboring the TP53 Y220C mutation, is under investigation in the PYNNACLE study, a Phase 1/2 clinical trial (NCT04585750). This first-in-class agent is being evaluated both as a monotherapy and in combination with pembrolizumab in patients with locally advanced or metastatic solid tumors characterized by the specific TP53 Y220C mutation.
PYNNACLE Study Design
The PYNNACLE study is an open-label, multicenter trial. The Phase 1 portion aimed to establish a safe and tolerable dose of rezatapopt, while also examining its pharmacokinetics, safety profile, and early signs of efficacy. Enrollment for the Phase 1 monotherapy arm is now complete. Subsequently, a Phase 1b segment assessed the combination of rezatapopt with pembrolizumab; enrollment in this combination therapy arm has also concluded.
The Phase 2 portion of the study is actively enrolling patients. This phase is designed to further evaluate the efficacy of rezatapopt as a single agent, alongside continued monitoring of its safety, pharmacokinetics, and impact on patient quality of life.
Significance of TP53 Y220C Mutation
The TP53 Y220C mutation is a specific alteration in the TP53 gene, which is a well-known tumor suppressor gene. This mutation can lead to a dysfunctional p53 protein, impairing its ability to regulate cell growth and division, and increasing the likelihood of tumor development. Rezatapopt selectively targets and reactivates the p53 protein specifically in tumors with the Y220C mutation, potentially restoring its tumor-suppressing function.
