PYNNACLE Trial with Rezatapopt (PC14586): A New Treatment for Advanced Tumors with the TP53 Y220C Mutation

Solid tumors are firm growths consisting of abnormally altered cells that grow in specific organs or tissues. Unlike blood cancers, such as leukemia, they do not form cells in the blood or bone marrow. Solid tumors can be benign or malignant and affect, for example, the lungs, breast, liver, or intestines. This study includes malignant, locally advanced, or solid tumors with distant metastases. The body contains special proteins, known as tumor suppressor proteins, that monitor cell growth and ensure that cells divide in a controlled manner. If the genes that control these protective proteins are altered—for example, due to mutations—this function can be lost. This increases the risk that cells will multiply uncontrollably, leading to cancer. One of the most important of these genes is the TP53 gene, which plays a crucial role in many types of cancer. It normally ensures that damaged cells are stopped or broken down before they divide further. However, if the gene is mutated, this protective mechanism no longer functions. In particular, the Y220C mutation causes the p53 protein to lose its structure and prevents it from functioning properly. This mutation occurs in various types of cancer—for example, ovarian, lung, breast, or uterine cancer.

Rezatapopt (also known as PC14586) is a novel drug developed specifically to target this Y220C mutation. It specifically binds to the altered site on the p53 protein and restores its normal structure and function to inhibit tumor growth. It is taken in tablet form. The goal of the PYNNACLE study is to investigate, in two phases, the safety and efficacy of Rezatapopt in people with solid tumors. It is an open-label, non-randomized Phase 1/2 study, meaning that all participants are aware of the treatment. The first phase has already been completed and tested various doses of Rezatapopt alone and in combination with pembrolizumab—an immunotherapy—to determine the maximum tolerated dose. The second phase is now underway, in which Rezatapopt is being evaluated as a monotherapy in patients with a TP53 Y220C mutation and no KRAS mutation. In this phase, study participants are divided into 5 cohorts based on their underlying disease: ovarian cancer, lung cancer, breast cancer, uterine cancer, and other solid tumors. All participants receive the same treatment. The primary endpoint in Phase 2 is how frequently and to what extent the tumors respond to the drug (tumor response rate). These measurements are taken up to 34 months after the start of Phase 2.

Women and men over the age of 18, and under certain conditions adolescents as young as 12, are eligible to participate in the study. Patients must have a locally advanced or metastatic solid tumor with a TP53 Y220C mutation. They must not have a KRAS mutation. Previous treatment must have already been completed.