Trial: The Evaluation of PC14586 in Patients W…

Trial Details

Sponsor: PMV Pharmaceuticals, Inc (industry)

Phase: 1/2

Start date: Oct. 29, 2020

Planned enrollment: 230

Trial ID: NCT04585750

More trial details at ClinicalTrials.gov

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: rezatapopt (PC14586)

Rezatapopt (PC14586) is a first-in-class, small molecule p53 reactivator specifically designed to target the TP53 Y220C mutation, which accounts for approximately 1.8% of all TP53 mutations in human cancers [1]. The drug works by selectively binding to a structural pocket created by the Y220C mutation, stabilizing the p53 protein in its wild-type conformation and restoring its tumor-suppressing function [2]. This mechanism is significant because p53 mutations are found in over 50% of human cancers, and until rezatapopt, no agents that selectively reactivate specific mutant p53 variants had been developed.

Efficacy and Safety

In the Phase 1 portion of the PYNNACLE trial (NCT04585750), rezatapopt demonstrated promising anti-tumor activity across multiple solid tumor types harboring the TP53 Y220C mutation. At the recommended Phase 2 dose of 2000 mg daily, the confirmed overall response rate was 38% (6/16 evaluable patients) in patients with TP53 Y220C mutations and KRAS wild-type tumors [3]. In a subgroup of 15 patients with advanced ovarian cancer, seven achieved a confirmed partial response with a median duration of response of seven months [4]. The drug has shown efficacy in various tumor types including ovarian, breast, prostate, lung, and endometrial cancers. Regarding safety, treatment-related adverse events were mostly grade 1 and 2, with the most frequent being nausea (51%), vomiting (43%), and increased blood creatinine (27%). Administration with food improved gastrointestinal side effects [4].

Rezatapopt is currently being evaluated in the registrational Phase 2 portion of the PYNNACLE trial as monotherapy in patients with TP53 Y220C-mutated and KRAS wild-type advanced solid tumors across five cohorts (ovarian, lung, breast, endometrial, and other solid tumors) [5]. A combination cohort with pembrolizumab was discontinued due to dose-limiting toxicities and lack of clinical benefit. The FDA has granted Fast Track designation to rezatapopt for the treatment of patients with locally advanced or metastatic solid tumors with a p53 Y220C mutation. Additionally, a new Phase 1b study is planned to assess rezatapopt alone and in combination with azacitidine in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) harboring the TP53 Y220C mutation.

Sources:

[1] Article in ACS Medicinal Chemistry Letters about rezatapopt development [2] PMC article on rezatapopt as p53 Y220C reactivator [3] PMV Pharmaceuticals press release on Phase 1 data [4] Data from SGO Annual Meeting on rezatapopt in ovarian cancer [5] OncLive article on rezatapopt development status

Last updated: Apr 2025

HealthScout AI Analysis

Goal: The goal of this trial is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of rezatapopt (PC14586), a selective p53 reactivator, as monotherapy and in combination with pembrolizumab in patients with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation.

Patients: Eligible patients are adults, and selected adolescents after additional review, with locally advanced or metastatic solid tumors that have a documented TP53 Y220C mutation, who have progressed after at least one prior line of therapy, with ECOG 0-1 and measurable disease by RECIST v1.1. Specific cohorts include ovarian, lung, breast, endometrial, and other solid tumors, with KRAS wild-type required for some parts. Exclusion criteria address uncontrolled comorbidities, recent anti-cancer therapy, and certain molecular features (e.g., KRAS mutations in phase 2).

Design: This is a multicenter, open-label, non-randomized phase 1/2 study. The phase 1 dose escalation portion evaluates rezatapopt monotherapy and in combination with pembrolizumab to determine safety, pharmacokinetics, and the recommended phase 2 dose (RP2D). Dose expansion and phase 2 focus on selected tumor types for efficacy.

Treatments: The investigational agent rezatapopt (PC14586) is a first-in-class, oral small molecule specifically designed to restore wild-type function to p53 protein in tumors with the Y220C mutation by binding to the mutant-specific structural pocket. In the phase 1 portion, rezatapopt has shown promising anti-tumor activity, especially in ovarian cancer (confirmed partial responses in 47% of evaluable patients with a median duration of response of 7 months), with the most common adverse events being grade 1-2 gastrointestinal effects that are mitigated by administration with food. Combination cohorts with pembrolizumab were discontinued after observing dose-limiting toxicities and lack of added benefit. The phase 2 monotherapy cohort is evaluating rezatapopt at the RP2D (2000 mg daily) in multiple solid tumors.

Outcomes: Primary outcomes include safety (adverse events and dose-limiting toxicities), determination of maximum tolerated dose and RP2D in phase 1, and overall response rate per independent central review in phase 2. Secondary outcomes include pharmacokinetic parameters, disease control rate, time to response, duration of response, progression-free survival, overall survival, and quality of life.

Burden on patient: Patient burden is moderate and typical for early phase trials of oral targeted agents. Participants can expect frequent clinical and laboratory assessments, regular imaging (often every 8-12 weeks), and intensive pharmacokinetic blood sampling, particularly during initial cycles. Adverse event monitoring and quality-of-life assessments are routine. As the agent is oral, travel is limited primarily to study visits rather than frequent drug administration, but phase 1 patients may require more intensive monitoring and blood draws for PK sampling, especially during dose escalation.

Eligibility

Show Criteria

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 28 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, 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

* 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

Sites (81)

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Chris O'Brien Lifehouse Hospital

Camperdown, New South Wales, Australia

No email / No phone

Status: Recruiting

Mater Cancer Care Centre

South Brisbane, Queensland, Australia

No email / No phone

Status: Not yet recruiting

Flinders Medical Center

Bedford Park, South Australia, Australia

No email / No phone

Status: Recruiting

Monash Medical Centre

Clayton, Victoria, Australia

No email / No phone

Status: Recruiting

Linear Clinical Research

Nedlands, Western Australia, Australia

No email / No phone

Status: Recruiting

ICANS - Institut de cancérologie Strasbourg Europe

Strasbourg, Bas-Rhin, France

No email / No phone

Status: Recruiting

Institut Bergonie

Bordeaux, Gironde, France

No email / No phone

Status: Recruiting

Institut Claudius Regaud

Toulouse, Haute-Garonne, France

No email / No phone

Status: Recruiting

EDOG Institut de Cancerologie de l'Ouest

Saint-Herblain, Loire-Atlantique, France

No email / No phone

Status: Recruiting

Centre Jean Perrin

Clermont-Ferrand, Puy-de-Dôme, France

No email / No phone

Status: Recruiting

Institut Gustave Roussy

Villejuif, Val-de-Marne, France

No email / No phone

Status: Recruiting

Centre Léon Bérard Centre Régional de Lutte Contre Le Cancer

Lyon, France

No email / No phone

Status: Recruiting

Institute Cancer De Lorraine

Vandœuvre-lès-Nancy, 54519, France

No email / No phone

Status: Recruiting

CHU de Nîmes

Nîmes, 30900, France

No email / No phone

Status: Recruiting

Nationale Centrum für Tumorerkrankungen (NCT) Heidelberg

Heidelberg, Baden-Württemberg, Germany

No email / No phone

Status: Recruiting

Universitätsklinikum Augsburg

Augsburg, Bayern, Germany

No email / No phone

Status: Recruiting

Universitätsklinikum Frankfurt

Frankfurt, Hessen, Germany

No email / No phone

Status: Recruiting

Universitätsklinikum Essen

Essen, Nordrhein-Westfalen, Germany

No email / No phone

Status: Recruiting

Asklepios Klinik Altona

Hamburg, Germany

No email / No phone

Status: Recruiting

Istituti Fisioterapici Ospitalieri - Istituto Nazionale Tumori Regina Elena

Rome, Lazio, Italy

No email / No phone

Status: Recruiting

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Rome, Lazio, Italy

No email / No phone

Status: Recruiting

Istituto Clinico Humanitas

Rozzano, Lombardia, Italy

No email / No phone

Status: Recruiting

Fondazione IRCCS Istituto Nazionale Dei Tumori

Milano, Lombardia, Italy

No email / No phone

Status: Recruiting

ASST Grande Ospedale Metropolitano Niguarda

Milano, Lombardia, Italy

No email / No phone

Status: Recruiting

Istituto Europeo Di Oncologia

Milano, Lombardia, Italy

No email / No phone

Status: Recruiting

Fondazione del Piemonte per l'Oncologia (IRCCS)

Candiolo, Torino, Italy

No email / No phone

Status: Recruiting

IRCCS - lstituto Nazionale Tumori - Fondazione G. Pascale

Napoli, 80131, Italy

No email / No phone

Status: Recruiting

Severance Hospital Yonsei University

Seoul, Korea, Republic of

No email / No phone

Status: Not yet recruiting

Samsung Medical Center

Seoul, Korea, Republic of

No email / No phone

Status: Not yet recruiting

National Cancer Center

Seoul, Korea, Republic of

No email / No phone

Status: Not yet recruiting

Asan Medical Center

Seoul, Korea, Republic of

No email / No phone

Status: Recruiting

Seoul University Hospital

Seoul, Korea, Republic of

No email / No phone

Status: Recruiting

National University Hospital

Kent Ridge, Singapore

No email / No phone

Status: Recruiting

National Cancer Center of Singapore

Singapore, 168582, Singapore

No email / No phone

Status: Recruiting

Instituto de Investigacion Oncologica Vall d'Hebron (VHIO) - EPON

Barcelona, Spain

No email / No phone

Status: Recruiting

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

No email / No phone

Status: Recruiting

NEXT Oncology-Hospital Quironsalud Barcelona

Barcelona, Spain

No email / No phone

Status: Recruiting

Hospital Clinico Universitario de Valencia

Valencia, Spain

No email / No phone

Status: Recruiting

START Rioja

Rioja, Spain

No email / No phone

Status: Not yet recruiting

START MADRID_Hospital Universitario HM Sanchinarro - CIOCC

Madrid, Spain

No email / No phone

Status: Recruiting

START MADRID_Hospital Universitario Fundacion Jimenez Diaz

Madrid, Spain

No email / No phone

Status: Recruiting

Sarah Cannon Research Institute UK

London, Middlesex, United Kingdom

No email / No phone

Status: Recruiting

Freeman Hospital

Newcastle Upon Tyne, Tyne and Wear, United Kingdom

No email / No phone

Status: Recruiting

University of California Irvine Chao Family Comprehensive Cancer Center

Irvine, California, 92868, United States

No email / No phone

Status: Not yet recruiting

Hoag Cancer Center

Irvine, California, 92618, United States

No email / No phone

Status: Withdrawn

UCLA Jonsson Comprehensive Cancer Center

Los Angeles, California, 90024, United States

No email / No phone

Status: Not yet recruiting

USC Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

No email / No phone

Status: Recruiting

University of San Francisco

San Francisco, California, 94143, United States

No email / No phone

Status: Withdrawn

Rocky Mountain Cancer Center

Denver, Colorado, 80218, United States

No email / No phone

Status: Recruiting

Yale Cancer Center

New Haven, Connecticut, 06519, United States

No email / No phone

Status: Recruiting

Medical Oncology Hematology Consultants

Newark, Delaware, 19713, United States

No email / No phone

Status: Recruiting

Florida Cancer Specialists South

Port Charlotte, Florida, 33980, United States

No email / No phone

Status: Recruiting

University of Miami - Sylvester Comprehensive Cancer Center

Miami, Florida, 33136, United States

No email / No phone

Status: Recruiting

Advent Health

Orlando, Florida, 32803, United States

No email / No phone

Status: Not yet recruiting

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Chicago, Illinois, 60611, United States

No email / No phone

Status: Not yet recruiting

Indiana University

Indianapolis, Indiana, 46240, United States

No email / No phone

Status: Withdrawn

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

No email / No phone

Status: Recruiting

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

No email / No phone

Status: Recruiting

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

No email / No phone

Status: Recruiting

New York University - Long Island Hospital

Mineola, New York, 11501, United States

No email / No phone

Status: Not yet recruiting

New York University Perlmutter Cancer Center

New York City, New York, 10016, United States

No email / No phone

Status: Not yet recruiting

Memorial Sloan Kettering

New York, New York, 10065, United States

No email / No phone

Status: Recruiting

Duke University

Durham, North Carolina, 27705, United States

No email / No phone

Status: Recruiting

The Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio, 44195, United States

No email / No phone

Status: Recruiting

University of Oklahoma

Oklahoma City, Oklahoma, 73104, United States

No email / No phone

Status: Recruiting

Oregon Health & Science University (OHSU)

Portland, Oregon, 97210, United States

No email / No phone

Status: Recruiting

WellSpan York Cancer Center

York, Pennsylvania, 17403, United States

No email / No phone

Status: Not yet recruiting

Abramson Cancer Center of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

No email / No phone

Status: Recruiting

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

No email / No phone

Status: Not yet recruiting

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

No email / No phone

Status: Recruiting

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

No email / No phone

Status: Recruiting

Vanderbilt University Medical Center - Ingram Cancer Center

Nashville, Tennessee, 37232, United States

No email / No phone

Status: Withdrawn

New Experimental Therapeutics of San Antonio - NEXT Oncology

San Antonio, Texas, 78229, United States

No email / No phone

Status: Recruiting

New Experimental Therapeutics - NEXT Oncology

Austin, Texas, 78705, United States

No email / No phone

Status: Recruiting

UTSW - Moody Outpatient Center - Parkland Health

Dallas, Texas, 75235, United States

No email / No phone

Status: Not yet recruiting

UT Southwest Simmons Cancer Center

Dallas, Texas, 75390, United States

No email / No phone

Status: Not yet recruiting

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

No email / No phone

Status: Recruiting

Virginia Cancer Specialists

Fairfax, Virginia, 22031, United States

No email / No phone

Status: Recruiting

Swedish Medical Center

Seattle, Washington, 98122-, United States

No email / No phone

Status: Not yet recruiting

University of Washington, Fred Hutchinson Cancer Center

Seattle, Washington, 98109, United States

No email / No phone

Status: Recruiting

University of Wisconsin Carbone Cancer Center

Madison, Wisconsin, 53705, United States

No email / No phone

Status: Recruiting

A Phase 1/2 Open-label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of PC14586 in Patients With Locally Advanced or Metastatic Solid Tumors Harboring a TP53 Y220C Mutation (PYNNACLE)

Trial Details

Show Summary from Sponsor

More details:

Investigational Drug AI Analysis

Show for: rezatapopt (PC14586)

Efficacy and Safety

Sources:

HealthScout AI Analysis

Eligibility

Show Criteria

Sites (81)

Chris O'Brien Lifehouse Hospital

Mater Cancer Care Centre

Flinders Medical Center

Monash Medical Centre

Linear Clinical Research

ICANS - Institut de cancérologie Strasbourg Europe

Institut Bergonie

Institut Claudius Regaud

EDOG Institut de Cancerologie de l'Ouest

Centre Jean Perrin

Institut Gustave Roussy

Centre Léon Bérard Centre Régional de Lutte Contre Le Cancer

Institute Cancer De Lorraine

CHU de Nîmes

Nationale Centrum für Tumorerkrankungen (NCT) Heidelberg

Universitätsklinikum Augsburg

Universitätsklinikum Frankfurt

Universitätsklinikum Essen

Asklepios Klinik Altona

Istituti Fisioterapici Ospitalieri - Istituto Nazionale Tumori Regina Elena

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Istituto Clinico Humanitas

Fondazione IRCCS Istituto Nazionale Dei Tumori

ASST Grande Ospedale Metropolitano Niguarda

Istituto Europeo Di Oncologia

Fondazione del Piemonte per l'Oncologia (IRCCS)

IRCCS - lstituto Nazionale Tumori - Fondazione G. Pascale

Severance Hospital Yonsei University

Samsung Medical Center

National Cancer Center

Asan Medical Center

Seoul University Hospital

National University Hospital

National Cancer Center of Singapore

Instituto de Investigacion Oncologica Vall d'Hebron (VHIO) - EPON

Hospital Universitario 12 de Octubre

NEXT Oncology-Hospital Quironsalud Barcelona

Hospital Clinico Universitario de Valencia

START Rioja

START MADRID_Hospital Universitario HM Sanchinarro - CIOCC

START MADRID_Hospital Universitario Fundacion Jimenez Diaz

Sarah Cannon Research Institute UK

Freeman Hospital

University of California Irvine Chao Family Comprehensive Cancer Center

Hoag Cancer Center

UCLA Jonsson Comprehensive Cancer Center

USC Norris Comprehensive Cancer Center

University of San Francisco

Rocky Mountain Cancer Center

Yale Cancer Center

Medical Oncology Hematology Consultants

Florida Cancer Specialists South

University of Miami - Sylvester Comprehensive Cancer Center

Advent Health

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Indiana University

Massachusetts General Hospital

Dana Farber Cancer Institute

Karmanos Cancer Institute

New York University - Long Island Hospital

New York University Perlmutter Cancer Center

Memorial Sloan Kettering

Duke University

The Cleveland Clinic Taussig Cancer Center

University of Oklahoma

Oregon Health & Science University (OHSU)

WellSpan York Cancer Center

Abramson Cancer Center of the University of Pennsylvania