Recruiting

The Evaluation of PC14586 in Patients With Advanced Solid Tumors Harboring a TP53 Y220C Mutation (PYNNACLE)

The Phase 2 monotherapy portion of this study is currently enrolling and will evaluate the efficacy and safety of PC14586 (INN rezatapopt) in participants with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation. The Phase 1 portion of the study will assess the safety, tolerability and preliminary efficacy of multiple dose levels of rezatapopt as monotherapy and in Phase 1b in combination with pembrolizumab.

ClinicalTrials.gov IDNCT04585750

PhasePHASE1, PHASE2

Enrollment300

SponsorPMV Pharmaceuticals, Inc

Age12 Years

SexALL

I'm interested View official listing

Conditions studied

Advanced Solid Tumor, Advanced Malignant Neoplasm, Metastatic Cancer, Metastatic Solid Tumor, Lung Cancer, Ovarian Cancer, Endometrial Cancer, Prostate Cancer, Colorectal Cancer, Breast Cancer, Other Cancer, Locally Advanced, Head and Neck Cancer, Gall Bladder Cancer, Small Cell Lung Cancer, Small Cell Lung Cancer ( SCLC ), Small Cell Lung Carcinoma, NSCLC, NSCLC (Non-small Cell Lung Cancer), SCLC, Non-Small Cell Lung Carcinoma, Triple Negative Breast Cancer, TNBC, HER2+ Breast Cancer, Non-Small Cell Lung Cancer, ER/PR Positive Breast Cancer, HER2- Breast Cancer, HER2-positive Breast Cancer, HER2-negative Breast Cancer, ER/PR(+), Her2(-) Breast Cancer

About this study

Interventions

Drug: rezatapopt — First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.
Drug: pembrolizumab — Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.

Primary outcomes

Phase 1 Monotherapy (Dose Escalation): Determine the number and type of adverse events to characterize the safety of rezatapopt (40 months)
Phase 1 Monotherapy (Dose Escalation): Establish the Recommended Phase 2 Dose (RP2D) (30 months)
Phase 1 Monotherapy (Dose Escalation): Establish the maximum tolerated dose (MTD) (Phase 1) (The first 28 days of treatment (Cycle 1) per patient)
Phase 1b Combination Therapy (Part 1: Dose Escalation): Determine the number and type of adverse events to characterize the safety of rezatapopt when administered in combination with pembrolizumab (18 months for treatment arm)
Phase 1b Combination Therapy (Part 1: Dose Escalation): Establish the maximum tolerated dose (MTD) of rezatapopt when administered in combination with pembrolizumab (The first 28 days of combination treatment arm (starting on Day -7) per patient)
Phase 1b Combination Therapy (Part 1: Dose Escalation): Establish the Recommended Phase 2 Dose (RP2D) of rezatapopt when administered in combination with pembrolizumab (18 months)
Phase 1b Combination Therapy (Part 2: Dose Expansion): Determine the number and type of adverse events to characterize the safety of rezatapopt when administered in combination with pembrolizumab (12 months for treatment arm)
Phase 2 Monotherapy (Dose Expansion): Response rate assessment to evaluate the clinical activity / efficacy of rezatapopt (34 months)

Eligibility information

Inclusion Criteria: * At least 18 years of age or 12 to 17 years of age after Safety Review Committee approval. * Locally advanced or metastatic solid malignancy with a TP53 Y220C mutation * Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 * Previously treated with one or more lines of anticancer therapy and progressive disease * Adequate organ function * Measurable disease per RECIST v1.1 (Phase 2) Additional Criteria for Inclusion in Phase 1b (rezatapopt) + pembrolizumab combination) * Anti-PD-1/PD-L1 naive or must have progressed on treatment * Measurable disease Exclusion Criteria: * Anti-cancer therapy within 21 days (or 5 half-lives) of receiving the study drug * Radiotherapy within 14 days of receiving the study drug * Primary CNS tumor * History of leptomeningeal disease or spinal cord compression * Brain metastases, unless neurologically stable and do not require steroids to treat associated neurological symptoms * Stroke or transient ischemic attack within 6 months prior to screening * Heart conditions such as unstable angina within 6 months prior to screening, uncontrolled hypertension, a heart attack within 6 months prior to screening, congestive heart failure, prolongation of QT interval, or other rhythm abnormalities * Strong CYP3A4 inducers and strong CYP2C9 inhibitors/inducers within 14 days of first dose of rezatapopt * History of gastrointestinal (GI) disease that may interfere with absorption of study drug or patients unable to take oral medication * History of prior organ transplant * Known, active malignancy, except for treated cervical intraepithelial neoplasia, or non-melanoma skin cancer * Known, active uncontrolled Hepatitis B, Hepatitis C, or human immunodeficiency virus infection Additional Criteria for Exclusion from Phase 2 (rezatapopt monotherapy) * Known KRAS mutation, defined as a single nucleotide variant (SNV) (Phase 2) Additional Criteria for Exclusion from Phase 1b (rezatapopt) + pembrolizumab combination) * Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor and discontinued from that treatment due to a Grade 3 or higher immune-related AE (irAE) * Received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention * Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy within 7 days prior to the first dose of study drug * Hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients * Active autoimmune disease that has required systemic treatment in past 2 years * History of radiation pneumonitis * History of (non-infectious) or active pneumonitis / interstitial lung disease that required steroids * Active infection requiring systemic therapy * Known history of HIV infection * Has previously received rezatapopt

Study locations

University of California Irvine Chao Family Comprehensive Cancer Center, Irvine, California 92868 United States
University of San Diego Moores Cancer Center, La Jolla, California 92093 United States
UCLA Jonsson Comprehensive Cancer Center, Los Angeles, California 90024 United States
USC Norris Comprehensive Cancer Center, Los Angeles, California 90033 United States
Rocky Mountain Cancer Center, Denver, Colorado 80218 United States
Yale Cancer Center, New Haven, Connecticut 06519 United States
Medical Oncology Hematology Consultants, Newark, Delaware 19713 United States
University of Miami - Sylvester Comprehensive Cancer Center, Miami, Florida 33136 United States
Advent Health, Orlando, Florida 32803 United States
Florida Cancer Specialists South, Port Charlotte, Florida 33980 United States

Showing 10 of 77 reported sites. See the official listing for all locations.

Before you participate: Varda Clinical is an independent discovery tool, not the study sponsor or a medical provider. Eligibility can only be determined by the official study team. Discuss potential risks and benefits with a qualified healthcare professional.

Source: ClinicalTrials.gov. Record last refreshed by Varda Clinical: 2026-09-27.