PYNNACLE phase II clinical trial protocol: rezatapopt (PC14586) monotherapy in advanced or metastatic solid tumors with a TP53 Y220C mutation

ABSTRACT

Rezatapopt is an investigational, first-in-class p53 reactivator specific to the TP53 Y220C mutation that works to stabilize and restore wild-type p53 conformation and tumor suppressor function. PYNNACLE (NCT04585750) is a phase I/II, single-arm, multicenter, clinical trial assessing rezatapopt in patients with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation. PYNNACLE phase II is currently enrolling (target enrollment is ~  114 patients across five cohorts defined by tumor type) and assesses rezatapopt at the recommended phase II dose. Eligible patients are aged ≥18 years (at all global sites except ≥21 years in Singapore and ≥19 years in South Korea) or 12–17 years if weighing ≥40 kg (in Australia, South Korea [12–18 years], and USA only), with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation and that are KRAS wild-type. Patients must have received ≥1 prior line of systemic therapy or be ineligible for standard of care and have measurable disease at baseline. Patients with KRAS single nucleotide variants are excluded. Eligible patients receive oral rezatapopt at 2000 mg, once daily, taken with food, for continuous 21-day cycles. The primary endpoint is the overall response rate assessed by blinded independent central review.

Clinical trial registration

NCT04585750 (ClinicalTrials.gov).

Plain Language Summary

Rezatapopt is a new drug being tested in clinical trials to help treat people with advanced solid tumors that have a specific mutation (Y220C) of the TP53 gene. Rezatapopt is designed to target p53 proteins that do not function properly due to this mutation. This helps to restore the normal function of the p53 proteins, so they can work to stop cancer cells from growing and spreading. In the phase II PYNNACLE clinical trial, described here, the effectiveness and safety of rezatapopt will be tested in patients with different types of advanced cancer with a TP53 Y220C mutation and who do not have a single nucleotide variant mutation in the KRAS gene (KRAS wild-type). This trial is for adults (18 years of age and older) and teenagers (in selected countries) who have already tried other treatments for their cancer that did not work or have stopped working, or for those who are not eligible to have the standard treatments that are available. To join this clinical trial, patients need to have solid tumors that can be measured. Participants will take rezatapopt once a day with food, over 21-day cycles. Doctors will closely monitor how the cancer responds to the rezatapopt treatment and will check for any side effects. This phase II clinical trial is already underway in several countries and will include around 114 patients.

1. Introduction

TP53, encoding the p53 tumor suppressor protein, is the most frequently mutated gene in human cancers, with mutations found in ~ 59% of all solid tumors [1–5]. TP53 mutations are frequently observed in subtypes of cancers with a more aggressive nature (such as triple-negative breast cancer, high-grade serous ovarian cancer, and small cell lung cancer) [1–6]. Most TP53 mutations (85–90%) are missense mutations that result in a full-length mutated p53 protein resulting in loss or alteration of p53 function [2,5,7]. The most common TP53 missense mutations occur in the central DNA-binding domain of p53, with the 10 most frequent referred to as “hot-spot” mutations that account for ~ 30% of all TP53 mutations [2,5,8]. These mutations either disrupt p53-DNA binding directly or result in local or global changes in the p53 protein structure, meaning that p53 can no longer bind to DNA [5,9]. The TP53 Y220C mutation is a key hot-spot TP53 missense mutation present in ~ 1% of all solid tumors [1,6,10]. This mutation destabilizes the p53 protein by creating a narrow, well-defined, hydrophobic pocket on the surface of the DNA-binding domain, near the site of the mutation [6,11–13]. This pocket increases the thermodynamic instability of the p53 protein and reduces the melting temperature, leading to rapid unfolding of the protein and aggregation under physiologic conditions [6,11–13]. The denatured Y220C-mutated p53 protein is unable to bind to DNA; thus, p53 tumor suppressor functions are lost, allowing growth and proliferation of tumor cells and oncogenic progression [11].

p53 mutations have generally been considered “undruggable,” as they do not have typical drug-binding sites [14]. However, in recent years, the development of small molecules with different mechanisms of action have shown promise in targeting mutated p53 [15]. For example, a small molecule targeting the TP53 R175H mutation was found to enhance the zinc affinity of p53 and restabilize the mutated protein [15]. Other strategies to stabilize the mutated p53 protein have included covalently modifying cysteine residues in the mutated p53 protein or chaperoning the DNA-binding domain to refold the protein [16]. Other small molecules act to prevent the mutated p53 from inhibiting downstream tumor suppressive proteins such as p73 [15]. For the TP53 Y220C mutation, the pocket created by the mutation is a possible target site for a mutation-selective targeted treatment [6,17–21]. While various strategies for targeting mutated p53 have been assessed preclinically, only a few p53-targeted therapeutic agents have progressed to advanced clinical trial phases, and none have reached regulatory approval as of yet [11]. While there have been other investigational p53-targeted agents that have been developed, most have been nonspecific, targeting multiple mutated forms of p53 and/or wild-type p53, and none as of yet have demonstrated activity in clinical studies. More recent strategies target either a single p53 mutation or subset of p53 mutations with similar phenotypes, with some agents in a very early phase of clinical development [22].

Rezatapopt is an investigational, first-in-class, selective p53 reactivator specific to the TP53 Y220C mutation that binds with high affinity to the mutated p53 Y220C protein and stabilizes the protein structure in the wild-type p53 conformation [18,20,23]. Rezatapopt was designed to fit tightly into the pocket via noncovalent hydrogen bonding, which enhances hydrophobic and van der Waals interactions, stabilizing the mutated p53 Y220C protein in the wild-type conformation, and restoring p53 transcriptional activity and tumor suppressor functions (Figure 1) [18,20]. Once p53 tumor suppressor functions are restored, cell-cycle inhibition and apoptosis are induced in tumor cells harboring the TP53 Y220C mutation [24].

Figure 1.

Graphical representation of the mechanism of action of rezatapopt [18,20,23,25].

Rezatapopt binds with high affinity to the mutated p53 Y220C protein and stabilizes the protein structure in the wild-type p53 conformation [18,20,23]. The TP53 Y220C mutation creates a pocket in the mutated protein [6,11–13]. Rezatapopt fits tightly into this pocket via noncovalent hydrogen bonding, which enhances hydrophobic and van der Waals interactions, stabilizing the mutated p53 Y220C protein in the wild-type conformation and restoring p53 transcriptional activity and tumor suppressor functions [18,20]. For further information around the mechanism of action of rezatapopt, including molecular dynamic studies and binding assays, please see references 18 and 20 [18,20].

PYNNACLE (NCT04585750; registration date: 1 October 2020) is a phase I/II, open-label, single-arm, multicenter clinical trial investigating rezatapopt in patients with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation [25].

The phase II part of the PYNNACLE clinical trial is ongoing and is currently enrolling. Here, we describe the study design for the PYNNACLE phase II pivotal trial assessing rezatapopt at the recommended phase II dose (RP2D), established in the PYNNACLE phase I clinical trial. The PYNNACLE phase II clinical trial is a single-arm, open-label, multicenter basket trial assessing rezatapopt in patients with solid tumors who harbor a TP53 Y220C mutation, identified by historical genomic analysis, and who do not have KRAS single nucleotide variant (SNV) mutations (Figure 2). PYNNACLE phase II is enrolling across ~ 70 clinical sites worldwide (Figure 3), with ~ 114 patients planned to be enrolled [26]. Enrollment began in March 2024 and is estimated to be completed by the end of 2025 [26,27].

Figure 2.

PYNNACLE phase II clinical trial study design and timeline of key events over the study period [26].

*Platinum resistant or refractory.

^†For all global sites except Singapore (aged ≥21 years) and South Korea (aged ≥19 years).

^‡Screening assessments will be performed within 14 days of the first rezatapopt dose (Cycle 1 Day 1), except for baseline disease scans (computed tomography/magnetic resonance imaging scans), which will be conducted within 28 days.

QD, once daily.

Figure 3.

Planned global recruitment sites for the phase II PYNNACLE clinical trial [26].

2. Methods

In the PYNNACLE phase II clinical trial, eligible patients are enrolled to one of the five cohorts defined by tumor type. Cohorts were selected based on the tumor types in which rezatapopt has shown the highest activity; this included ovarian cancer, lung cancer, breast cancer, and endometrial cancer. An additional cohort includes patients with all other solid tumors (except primary central nervous system tumors).

Approximately 114 patients are expected to be enrolled for the primary analysis across the five patient cohorts, with ~ 42 patients planned for the ovarian cancer cohort, and ~ 18 patients for each of the lung cancer, breast cancer, endometrial cancer, and other solid tumor cohorts.

All patients must meet the following criteria to be eligible to participate in the PYNNACLE phase II clinical trial:

• ≥18 years of age for all global sites except Singapore (must be ≥21 years of age) and South Korea (must be ≥19 years of age), or 12–17 years of age if weighing ≥40 kg (in Australia, South Korea [12–18 years of age], and USA only)

• Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1

• Confirmed locally advanced or metastatic solid tumor with a TP53 Y220C mutation identified through next-generation sequencing (NGS) using a Sponsor-approved assay

  • Only NGS assays that meet the pre-specified analytical performance criteria are considered Sponsor-approved tests. Use of a Sponsor-approved test minimizes the risk of a false test result to ensure accurate identification of patients whose tumors harbor the TP53 Y220C mutation; this will ensure that the TP53 Y220C mutation identified is derived from the tumor and not a result of suspected clonal hematopoiesis of indeterminate potential (CHIP).
  • CHIP is a common age-related phenomenon in which hematopoietic stem cells or other early blood cell progenitors contribute to the formation of a genetically distinct subpopulation of blood cells [28]. CHIP can account for up to 25% to 40% of TP53 variants detected in saliva and blood during germline testing, requiring additional confirmatory testing [29]. There is a possibility that a liquid assay will detect TP53 Y220C that is derived from CHIP rather than a tumor if the assay does not assess for CHIP.

• Received prior standard therapy appropriate for their tumor type and stage or are ineligible for standard-of-care treatment according to the Investigator’s assessment, and have radiographic progression

• Measurable disease at baseline as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as assessed by the Investigator

• Adequate organ function

• Females of childbearing potential must have a negative pregnancy test within 3 days prior to treatment and must use a highly effective method of contraception during the trial or abstain from intercourse

• Males must abstain from intercourse or use a condom to prevent delivery of the drug via seminal fluid

• Must be willing to undergo a tumor biopsy during screening for NGS if a historical/archival tumor specimen is not available and if the biopsy procedure is in line with standard of care (i.e., of low risk to the patient and the tumor is of sufficient size to be biopsied)

• Life expectancy of at least 3 months as assessed by the Investigator

• Written patient consent obtained prior to any procedures, sampling, or analysis

Patients meeting any of the criteria below are ineligible to participate in the PYNNACLE phase II clinical trial:

• Has a known KRAS SNV mutation

  • KRAS mutations are associated with poor prognosis and tumorigenesis in various different types of cancer, and the co-occurrence of TP53 and KRAS mutations may have an even greater impact on tumor progression [30–35]
  • Furthermore, in the phase I portion of the PYNNACLE study, while some patients with gastrointestinal tumors with KRAS SNV mutations had a reduction in tumor volume, there were no confirmed partial or complete responses (per RECIST v1.1) in these patients
  • Based on the above information, patients with tumors that harbor known KRAS SNV mutations at baseline were excluded across all cohorts in the phase II PYNNACLE study

• Received prior chemotherapy, targeted therapy, immunotherapy, or treatment with an investigational anticancer agent within 21 days or five half-lives (if half-life is known), whichever is shorter, before receiving their first dose of rezatapopt

• Received radiotherapy within 14 days

• Primary central nervous system tumor

• Brain metastases, except for patients with neurologically stable brain metastases that do not require steroids to treat associated neurologic symptoms

• Had a stroke or transient ischemic attack within 6 months prior to screening

• A history of leptomeningeal disease or spinal cord compression, organ transplant, or gastrointestinal disease that may impact rezatapopt absorption

• Any heart conditions (unstable angina, uncontrolled hypertension, heart attack within 6 months prior to screening, heart failure, or other clinically significant rhythm abnormalities)

• Uncontrolled hepatitis B, hepatitis C, or HIV infection

• Received any of the following medications before the first dose of rezatapopt: strong cytochrome inducers (CYP3A4) within 14 days; inhibitors of P-glycoprotein or breast cancer resistance protein within 7 days

• Any medical condition, under the discretion of the Investigator, that may prevent participation in the clinical trial due to safety concerns or compliance with clinical trial procedures

• Any other known active malignancy, except for treated cervical intraepithelial neoplasia, or nonmelanoma skin cancer

Enrollment in the trial will be open to patients with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation identified by an approved molecular test/assay. Once the molecular test is reviewed and approved centrally by the Sponsor, the patient can proceed to the screening phase of the trial.

Before entering the clinical trial, written informed consent is obtained for each patient, and screening assessments are initiated. These include a review of the patient’s medical history, assessment of ECOG PS, physical examination, electrocardiogram, laboratory assessments, and tumor assessments by computed tomography, magnetic resonance imaging, and/or bone scan, and tumor histopathology. A tumor biopsy will be obtained during screening for NGS (if archival tumor tissue is not available) and potential biomarker evaluations. Tumor samples are required for genomic profiling to identify genomic alterations, including the TP53 Y220C mutation, across samples collected. If a tumor sample is unavailable or insufficient, then patients must be willing to undergo a tumor biopsy during screening if the procedure is low risk and the tumor is of sufficient size to be biopsied. Blood samples will be collected at screening or Day 1 and on treatment (every 3 or 9 weeks if the patient is on a reduced schedule) for exploratory longitudinal circulating tumor DNA monitoring. This will be an exploratory evaluation assessing the effects of rezatapopt on the tumor genomic profile over time. Screening assessments will be performed within 14 days of the first rezatapopt dose, except for computed tomography/magnetic resonance imaging scans, which will be conducted within 28 days of the first dose.

Following overall safety, efficacy, and pharmacokinetic (PK) data from the phase I dose escalation portion of the PYNNACLE study, as well as population pharmacokinetics, exposure-response models, and food effect analyses, the RP2D of rezatapopt was selected as 2000 mg once daily (QD) administered with food [21,36]. In these analyses, an increase in exposure was observed when rezatapopt 2000 mg QD was administered with food versus without food [21,36]. Furthermore, gastrointestinal adverse events (AEs) were reduced when rezatapopt 2000 mg was administered with food [21,36]. Therefore, in the PYNNACLE phase II trial, eligible patients will receive oral rezatapopt at the RP2D of 2000 mg QD with food for continuous 21-day cycles.

Patients may continue to receive rezatapopt for as long as they continue to show clinical benefit, as judged by the Investigator, or until disease progression or other treatment discontinuation criteria are met. Patients will be followed up until loss to follow-up, death, 2 years after the last patient discontinuation, or end of study.

2.1. Outcomes and endpoints

Tumor shrinkage as measured by overall response rate (ORR; per RECIST v1.1) in conjunction with duration of response can assess the viability of an investigational agent in a single-arm setting [37–39]. A randomized controlled trial would not be feasible in patients with solid tumors with a TP53 Y220C mutation, due to the rarity of the mutation and the different standard-of-care therapies per tumor type. Single-arm trials using response rate and duration of response to support an approval have historically been acceptable if the investigational treatment is intended for patients with refractory, advanced, or metastatic cancers, the agent targets a rare molecular alteration, and the results are clinically meaningful [40].

The primary objective of the PYNNACLE phase II clinical trial is to assess the efficacy of rezatapopt at the RP2D as assessed by blinded independent central review (BICR). The primary endpoint is the ORR according to RECIST v1.1 per BICR assessment across all cohorts and in the ovarian cancer cohort only.

Secondary objectives include assessment of the efficacy of rezatapopt at the RP2D as assessed by the Investigator; the safety and tolerability of rezatapopt; additional efficacy parameters; rezatapopt concentrations when administered orally; PK parameters; and quality of life.

Secondary endpoints will be analyzed across all cohorts and in the ovarian cancer cohort only and include ORR according to RECIST v1.1 as assessed by the Investigator; BICR and Investigator-assessed time to response, duration of response, disease control rate at 6, 12, 18, and 24 weeks, and progression-free survival according to RECIST v1.1; and overall survival. Time to response and duration of response are secondary endpoints in this study and will be supportive of the primary endpoint of ORR [41].

Safety endpoints will include incidence of AEs, serious AEs, changes in laboratory assessments, electrocardiogram, ECOG PS, vital signs, and physical exams.

PK endpoints will include rezatapopt plasma concentrations and plasma PK parameters, including maximum observed plasma concentration, time to maximum observed plasma concentration, area under the plasma concentration – time curve from time zero to time of last sampling timepoint, area under the plasma concentration – time curve in one dosing interval, and trough observed concentrations.

The effects of rezatapopt on quality of life will be evaluated via patient-reported outcomes collected using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) for patients aged ≥18 years. Quality of life will be assessed at baseline and on-treatment (aligning with the patient’s visit schedule).

Additional exploratory endpoints will include analyses of circulating tumor DNA at baseline and throughout treatment, use of NGS to characterize baseline genomics (co-mutations, including other TP53 mutations), the association between molecular/genomic profiles and clinical outcomes, as well as genomic changes and rezatapopt metabolite concentrations during treatment.

2.2. Statistical analysis

2.2.1. Primary endpoint

ORR will be estimated by observed response rate (according to RECIST v1.1), and 95% confidence intervals (CIs) will be calculated using the Blyth-Still-Casella method for exact CIs [42,43]. If the lower bound of the 95% CI is above the assumed ORR of standard of care (12% for ovarian cancer cohort; 15% for the overall population), then rezatapopt will be considered superior to standard of care in the ovarian cancer cohort and in the overall population, respectively. All time-to-event endpoints will be summarized descriptively using the Kaplan – Meier method. Analysis across cohorts will be performed once the enrolled patients have completed at least 6 months of treatment or have discontinued early. A similar analysis will be carried out for the ovarian cancer cohort only. Patients with measurable disease at baseline who receive at least one dose of rezatapopt and have one post-baseline tumor assessment will be evaluable for efficacy (efficacy evaluable population).

2.2.2. Secondary endpoints

AEs and laboratory results will be summarized using the Medical Dictionary for Regulatory Activities classification system, and severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. All AEs and serious AEs will be collected from the time a patient provides informed consent, up to 30 days after the last rezatapopt dose, and will be assessed for the relationship to study treatment. All patients who receive at least one dose of rezatapopt will be evaluable for safety (safety population).

Summary statistics for rezatapopt plasma concentration data will be summarized using nominal time points. Individual and mean concentrations versus nominal time plots will be presented. For plasma PK parameters, summary statistics will be presented as geometric means and coefficients of variation (or medians and ranges where appropriate) and plots versus time.

2.2.3. Sample size

Patients will be enrolled into one of the five different cohorts based on tumor type (ovarian cancer, lung cancer, breast cancer, endometrial cancer, and all other solid tumors), with an overall target enrollment of ~ 114 patients. Each tumor cohort may be analyzed separately or combined to potentially support a tumor-specific or tumor-agnostic indication, respectively. Approximately the same number of patients will be enrolled in each cohort (n = ~ 18) except for the ovarian cancer cohort, which will enroll more patients (n = ~ 42). The ovarian cancer subpopulation has a higher frequency of TP53 Y220C mutations compared with the other solid tumor cohorts and a high unmet medical need. Based on an anticipated higher enrollment rate for the ovarian cancer patients, more patients will be enrolled into this cohort to allow a separate well-powered analysis in the ovarian cancer subpopulation as part of the primary endpoint. With ~ 114 patients planned for the primary analysis across cohorts and assuming a true ORR of 30%, the average lower half-width of the 95% CI is 8.1%, reflecting the expected precision. Under this assumption, the study has 97.8% power to demonstrate that the lower limit of the 95% CI of the ORR exceeds 15%. If futility criteria are applied strictly, the power is reduced to 90.9%. With ~ 42 patients planned for the primary analysis in the ovarian cancer cohort, and assuming a true ORR of 30%, the expected precision in terms of the average lower half-width of the 95% CI is 12.4%. Under this assumption, the power is 85.0% to demonstrate that the lower limit of the 95% CI of the ORR exceeds 12%. If futility decisions are followed strictly, the power is reduced to 80.0%.

2.3. Limitations

Open-label, single-arm studies are prone to assessment bias, as investigators or patients may report more favorable outcomes due to expectations, potentially inflating efficacy or underreporting AEs [44]. To mitigate this, the primary endpoint of ORR is based on BICR assessment rather than Investigator assessment to minimize any potential bias for the primary analysis. In addition, sensitivity analyses will be conducted to test the robustness of the results under varying assumptions and, along with standardized protocols, defined endpoints, and statistical analysis plans, these will help to minimize performance and reporting biases [45].

3. Ethics and dissemination

The PYNNACLE clinical trial protocol (latest version: Nov 2024, v10.0/v10.1-EU) and any amendments, along with other trial-related documentation, have been or will be approved by the local institutional review board and independent ethics committee of participating centers prior to trial activation. This clinical trial will be conducted in accordance with all laws and regulations, and principles from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, International Council for Harmonisation Good Clinical Practice guidelines, and the European regulation for clinical trials. Written informed consent has been or will be obtained from all patients prior to any trial-related procedures being conducted. Study monitors will perform ongoing source data verification to confirm that data are accurate, complete, and verifiable from source documents; that the safety and rights of patients are being protected; and that the study is being conducted in accordance with the currently approved protocol and all applicable regulatory requirements. Records and documents related to this clinical trial will be retained by the Investigator for 10 years after completion, or up until the date that records are no longer needed, or unless local regulations or institutional policies require a longer retention period. Study results are planned to be disseminated in peer-reviewed journals and at scientific meetings.

4. Conclusion

Until now, small molecules developed to target the Y220C-mutated p53 protein have lacked the potency required for therapeutic application [11,22]. Rezatapopt, a first-in-class, selective p53 reactivator, represents a potential advancement in p53 Y220C reactivation. Rezatapopt stabilizes the endogenous Y220C-mutated p53 protein in the wild-type conformation by selectively binding to the pocket within the protein created by the mutation [18,20,23]. This restores the DNA binding activity and tumor suppression function of wild-type p53. In preclinical and clinical trials, rezatapopt has demonstrated enhanced specificity, potency, and clinical translatability in the treatment of solid tumors with a TP53 Y220C mutation [18,20,21,23].

The pivotal PYNNACLE phase II trial will assess rezatapopt as a monotherapy at the RP2D of 2000 mg QD taken with food in patients with TP53 Y220C-mutated and KRAS wild-type locally advanced or metastatic solid tumors.

A single-arm study design supporting a tumor-agnostic development approach is being utilized for the PYNNACLE phase II trial based on the rarity of the patient population and the lack of available targeted therapies for patients with advanced solid tumors that have a TP53 Y220C mutation. A randomized controlled trial was not considered to be feasible in this tumor-agnostic, rare patient population since a suitable control arm is not available due to the diversity of underlying diseases with different standards of care. Therefore, a single-arm study design using ORR and duration of response as key efficacy endpoints is justified in this rare population of patients with advanced solid tumors harboring a TP53 Y220C mutation.

Rezatapopt has the potential to address an unmet medical need and provide targeted treatment for patients with a range of locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation, particularly those who do not respond to current standard-of-care treatments [18,20,21,23].

Funding Statement

The PYNNACLE study is funded by PMV Pharmaceuticals, Inc, NJ, USA (info@pmvpharma.com). Medical writing and editorial support for this manuscript were provided by Lucretia Ramnath and Danielle Lindley of Nucleus Global, an Inizio company, in accordance with Good Publication Practice (GPP) 2022 guidelines (https://www.ismpp.org/gpp-2022), and was funded by PMV Pharmaceuticals, Inc.

Article highlights

• TP53 mutations result in the loss of p53 tumor suppressor functions, which leads to tumor development and progression.

• The TP53 Y220C mutation, occurring in ~ 1% of all solid tumors, creates a pocket on the surface of the mutated protein, causing p53 to destabilize and lose its tumor suppressor function.

• Rezatapopt is an investigational p53 reactivator, specific to the TP53 Y220C mutation, that works to stabilize and restore wild-type p53 conformation and tumor suppressor function.

• PYNNACLE phase II is a global, single-arm, pivotal basket trial assessing the efficacy and safety of rezatapopt at the recommended phase II dose (RP2D) in patients with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation and who are KRAS wild-type.

• Approximately 114 patients will be enrolled across five cohorts defined by tumor type, including ~ 42 patients with ovarian cancer and ~ 18 patients each with lung cancer, breast cancer, endometrial cancer, and other solid tumors.

• Rezatapopt will be administered orally at the RP2D of 2000 mg once daily with food for continuous 21-day cycles.

• The primary endpoint will assess the efficacy of rezatapopt by evaluating the overall response rate across all cohorts and in the ovarian cancer cohort only.

• Key secondary efficacy endpoints will include time to response, duration of response, disease control rate, progression-free survival, and overall survival.

• Other secondary endpoints will include safety, pharmacokinetics, and patient-reported outcomes/quality of life.

• Rezatapopt has the potential to provide targeted treatment for patients with locally advanced or metastatic solid tumors who have a TP53 Y220C mutation and are KRAS wild-type.

Author contributions

Alison M Schram and Ecaterina E Dumbrava: Conceptualization, Methodology, and Co-Principal Investigators of the PYNNACLE clinical trial. All authors: Writing – Original Draft preparation, Reviewing and Editing. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Disclosure statement

Alison M Schram reports attending advisory boards for Blueprint Medicines, Mersana, Endeavor Biomedicines, Revolution Medicine, Day One Biopharmaceuticals, Transcode Therapeutics, and Relay Therapeutics. Alison M Schram provided an advisory role for Merus, Pfizer, PMV Pharmaceuticals, Schrodinger, Repare Therapeutics, and Relay Therapeutics. Alison M Schram received research funding to the institution from ArQule, AstraZeneca, BeiGene/Springworks, Black Diamond, Boehringer Ingelheim, Elevation Oncology, Kura Oncology, Eli Lilly, Merus, Northern Biologics, Pfizer, PMV Pharmaceuticals, Relay Therapeutics, Repare, Revolution Medicine, and Surface Oncology.

Marc Fellous, Kim LeDuke, and Anita Schmid are employees of PMV Pharmaceuticals with stock options.

Ecaterina E Dumbrava reports receiving research or grant funding from Bayer HealthCare Pharmaceuticals Inc., Immunocore Ltd., Amgen, Aileron Therapeutics, Compugen Ltd., Gilead, BOLT Therapeutics, Aprea Therapeutics, Bellicum Pharmaceuticals, PMV Pharmaceuticals, Triumvira Immunologics, Seagen, Mereo BioPharma 5 Inc., Sanofi, Rain Oncology, Astex Therapeutics, Sotio, Poseida, Mersana Therapeutics, Genentech, Boehringer Ingelheim, Dragonfly Therapeutics, A2A Pharmaceuticals, Volastra, AstraZeneca, Fate Therapeutics, Pfizer, Jacobio, and Modex Therapeutics. Ecaterina E Dumbrava attended advisory boards for BOLT Therapeutics, Mersana Therapeutics, Orum Therapeutics, Summit Therapeutics, Fate Therapeutics, and PMV Pharmaceuticals. Ecaterina E Dumbrava provided a speaker role for PMV Pharmaceuticals and BOLT Therapeutics. Ecaterina E Dumbrava received travel, accommodation, and expenses funding from ASCO, LFSA Association, Rain Oncology, Banner MD Anderson Cancer Center, Triumvira Immunologics, KSMO, and Boehringer Ingelheim. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Ethics declaration

The PYNNACLE clinical trial protocol (latest version: Nov 2024, v10.0/v10.1-EU) and any amendments, along with other trial-related documentation, have been or will be approved by the local institutional review board and independent ethics committee of participating centers prior to trial activation. This clinical trial will be conducted in accordance with all laws and regulations, and principles from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, International Council for Harmonisation Good Clinical Practice guidelines, and the European regulation for clinical trials. Written informed consent has been or will be obtained from all patients prior to any trial-related procedures being conducted.