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

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.

Methods:

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.
PYNNACLE Phase 1/2 basket study (NCT04585750).

Patient population

N≈114 (planned)

Key inclusion criteria

 

Primary endpoints

 

Secondary endpoints

 

Cohort 1

Ovarian cancer
(platinum-resistant)

n≈42

 

Cohort 2

Lung cancer

n≈18

 

Cohort 3

Breast cancer

n≈18

 

Cohort 4

Endometrial cancer

n≈18

 

Cohort 5

Other solid tumors

n≈18

Adults aged ≥18 years (all global sites except ≥21 years in Singapore)

Adolescents aged 12–17 years if weight ≥40 kg
(90 lbs; Australia, South Korea and USA only)

Locally advanced or metastatic solid tumors

Documented TP53 Y220C mutation and KRAS wildtype*

Prior standard therapy or ineligible for appropriate standard of care therapy

ORR per BICR assessment (RECIST v1.1) across all cohorts

ORR per BICR assessment (RECIST v1.1) in ovarian cancer cohort

ORR per investigator assessment (RECIST v1.1) across all cohorts and the ovarian cancer cohort

Time to response,
duration of response,
disease control rate

Progression-free survival

Overall survival

Safety

Pharmacokinetics

Quality of life
* Defined as no KRAS single nucleotide variant.

BICR, blinded independent central review; ORR, objective response rate; 
RECIST v1.1, Response Evaluation Criteria in Solid Tumors Version 1.1.

Disclaimer

This material on this page is ©2025 American Society of Clinical Oncology, all rights reserved. Licensing available upon request. For more information, please contact licensing@asco.org

Author Details

Alison Schram

Alison Schram

Memorial Sloan Kettering Cancer Center, New York, NY

Abstract Details

Meeting

2025 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Sarcoma

Track

Sarcoma

View More

Abstract Disclosure