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)

Overview

Rezatapopt (PC14586) is an oral, first-in-class small-molecule designed to selectively reactivate the mutant p53 protein bearing the TP53 Y220C substitution. It is being studied in the ongoing, global, registrational Phase 2 portion of the Phase 1/2 PYNNACLE basket trial (NCT04585750) across multiple solid tumors with TP53 Y220C and KRAS wild-type status. The FDA has granted Fast Track designation for rezatapopt in locally advanced or metastatic solid tumors with a TP53 Y220C mutation. (oncologypro.esmo.org)

Mechanism of action

Target: TP53 Y220C mutant protein. The Y220C substitution creates a mutant-specific surface pocket that destabilizes p53. Rezatapopt binds this pocket, stabilizes native-like conformation, restores DNA binding and downstream transcriptional activity, and elicits antitumor effects in preclinical models (single-agent and in combination settings). (aacrjournals.org)
Medicinal chemistry/biophysical profile: Structure-based design yielded nanomolar biochemical potency to enhance p53 Y220C DNA binding and tumor growth inhibition in Y220C-driven models. (pubs.acs.org)

Efficacy

Phase 2 (interim, monotherapy; data cutoff August 4, 2025; dose 2000 mg once daily with food)

Overall: ORR 33% (32/97) per investigator (confirmed + unconfirmed), median time to response 1.4 months, median duration of response 6.2 months. Responses observed across 8 tumor types. (biospace.com)
Cohort-specific ORRs reported:
Ovarian cancer: 43% (19/44), including 1 confirmed complete response; median DoR 7.6 months. (biospace.com)
Lung cancer: 22% (4/18). (biospace.com)
Breast cancer: 18% (2/11). (biospace.com)
Endometrial cancer: 60% (3/5). (biospace.com)
Other solid tumors: 21% (4/19). (biospace.com)

Phase 1 (monotherapy; RP2D selection)

At the recommended Phase 2 dose (RP2D) of 2000 mg once daily, a confirmed ORR of 38% (6/16 evaluable patients reflective of the planned Phase 2 population) with median DoR of 7 months was reported. (pmvpharma.gcs-web.com)

Trial design notes

PYNNACLE Phase 2 is a single-arm, pivotal basket trial (planned n≈114) with ORR by blinded independent central review as the primary endpoint; adolescents (12–17 years, ≥40 kg) may enroll in selected countries. Dosing is 2000 mg once daily with food. KRAS single-nucleotide variant mutations are excluded. (oncologypro.esmo.org)

Safety

Phase 2 interim (monotherapy; 109 treated)

Most treatment-related adverse events (TRAEs) were grade 1–2. TRAEs >15%: nausea, fatigue, increased blood creatinine, increased ALT. Individual grade 3 TRAEs each <6%, all resolved on treatment. Discontinuations due to TRAEs: 3.7%. Administration with food improved gastrointestinal tolerability versus Phase 1. (biospace.com)

Combination cohort

A Phase 1b pembrolizumab combination cohort was discontinued due to dose-limiting toxicities and lack of clinical benefit; monotherapy development continues at 2000 mg QD. (onclive.com)

HealthScout AI Analysis

Goal: Assess safety, tolerability, pharmacokinetics/pharmacodynamics, and antitumor activity of the p53 Y220C-selective reactivator rezatapopt (PC14586) as monotherapy and, in Phase 1b, in combination with pembrolizumab; and determine RP2D/MTD. The Phase 2 monotherapy portion aims to establish efficacy, with ORR by blinded independent central review as the primary endpoint, including a dedicated ovarian cancer cohort and an all-cohort analysis.

Patients: Adults (and adolescents 12–17 years after approval) with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation, ECOG 0–1, previously treated with at least one prior line and with progressive disease, adequate organ function, and measurable disease for Phase 2. Exclusions include recent anticancer therapy or radiotherapy, unstable CNS disease, significant cardiovascular comorbidity, strong CYP3A4 inducers, malabsorption or inability to take oral therapy, active viral infections, prior organ transplant, and active second malignancy. Phase 2 excludes known KRAS SNVs. Phase 1b combination adds immunotherapy-specific exclusions (eg, severe prior immune-related AEs, active autoimmune disease requiring treatment, recent live vaccines, pneumonitis history).

Design: Open-label, multicenter, non-randomized Phase 1/2 study with sequential parts: Phase 1 monotherapy dose escalation to define MTD/RP2D; Phase 1b dose escalation and expansion of rezatapopt plus pembrolizumab; and Phase 2 monotherapy dose-expansion in tumor-specific cohorts. Enrollment target approximately 230 participants.

Treatments: Rezatapopt (PC14586) is an oral, first-in-class small-molecule p53 reactivator designed to selectively bind the Y220C-induced pocket in mutant p53, stabilizing a wild-type–like conformation and restoring tumor suppressor function in TP53 Y220C cancers. Early Phase 1 data at the RP2D of 2000 mg daily showed encouraging activity in KRAS wild-type, TP53 Y220C tumors with a confirmed ORR around the upper 30% range and notable responses in ovarian cancer; most treatment-related adverse events were grade 1–2, primarily gastrointestinal, mitigated by dosing with food. The agent is being pursued in a registrational-intent Phase 2 monotherapy program across ovarian, lung, breast, endometrial, and other solid tumors. Pembrolizumab is administered at 200 mg IV every 3 weeks in the Phase 1b combination cohorts to evaluate safety, PK, and preliminary efficacy of the combination.

Outcomes: Primary endpoints: Phase 1 and 1b—safety/tolerability, DLTs to define MTD and RP2D; Phase 2—overall response rate by BICR per RECIST v1.1 (overall and ovarian cohort). Secondary endpoints include comprehensive rezatapopt PK (Cmax, Tmax, AUC, trough), plasma concentrations of parent and metabolite, safety summaries, and antitumor activity measures (investigator- and BICR-assessed ORR, time to response, duration of response, disease control rate, progression-free survival, overall survival). Phase 2 also includes quality of life assessments in adults.

Burden on patient: Moderate to high. As a Phase 1/2 program, participants undergo frequent visits, serial PK blood draws, safety labs, ECGs, and imaging at regular intervals; Phase 1/1b parts typically require dense early PK sampling and DLT monitoring in Cycle 1. The oral regimen is daily and may require dosing with food, while combination cohorts add IV pembrolizumab every 3 weeks and infusion-related visit time. Eligibility-related genomic testing to confirm TP53 Y220C and serial RECIST assessments add travel and procedural burden. No mandatory biopsies are explicitly listed, which may reduce invasiveness, but overall visit frequency and PK requirements, especially early, remain substantial compared with standard care.

Last updated: Oct 2025

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 (82)

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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

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Flinders Medical Center

Bedford Park, South Australia, Australia

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Status: Recruiting

Monash Medical Centre

Clayton, Victoria, Australia

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Linear Clinical Research

Nedlands, Western Australia, Australia

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ICANS - Institut de cancérologie Strasbourg Europe

Strasbourg, Bas-Rhin, France

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Institut Bergonie

Bordeaux, Gironde, France

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Institut Claudius Regaud

Toulouse, Haute-Garonne, France

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EDOG Institut de Cancerologie de l'Ouest

Saint-Herblain, Loire-Atlantique, France

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Centre Jean Perrin

Clermont-Ferrand, Puy-de-Dôme, France

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Institut Gustave Roussy

Villejuif, Val-de-Marne, France

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Centre Léon Bérard Centre Régional de Lutte Contre Le Cancer

Lyon, France

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Institute Cancer De Lorraine

Vandœuvre-lès-Nancy, 54519, France

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Status: Recruiting

CHU de Nîmes

Nîmes, 30900, France

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Nationale Centrum für Tumorerkrankungen (NCT) Heidelberg

Heidelberg, Baden-Wurttemberg, Germany

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Universitätsklinikum Augsburg

Augsburg, Bavaria, Germany

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Status: Recruiting

Asklepios Klinik Altona

Hamburg, City state of Hamburg, Germany

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Status: Recruiting

Universitätsklinikum Frankfurt

Frankfurt am Main, Hesse, Germany

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Universitätsklinikum Essen

Essen, North Rhine-Westphalia, Germany

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Istituti Fisioterapici Ospitalieri - Istituto Nazionale Tumori Regina Elena

Rome, Lazio, Italy

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Status: Recruiting

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Rome, Lazio, Italy

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Istituto Clinico Humanitas

Rozzano, Lombardy, Italy

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Status: Recruiting

Istituto Europeo Di Oncologia

Milan, Lombardy, Italy

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Status: Recruiting

Fondazione IRCCS Istituto Nazionale Dei Tumori

Milan, Lombardy, Italy

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Status: Recruiting

ASST Grande Ospedale Metropolitano Niguarda

Milan, Lombardy, Italy

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Status: Recruiting

Fondazione del Piemonte per l'Oncologia (IRCCS)

Candiolo, Torino, Italy

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Status: Recruiting

IRCCS - lstituto Nazionale Tumori - Fondazione G. Pascale

Napoli, 80131, Italy

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Status: Recruiting

Humanitas San Pio X

Milan, Italy

No email / No phone

Status: Not yet recruiting

National Cancer Center of Singapore

Singapore, 168582, Singapore

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Status: Recruiting

National University Hospital

Kent Ridge, Singapore

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Status: Recruiting

Seoul University Hospital

Seoul, South Korea

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Status: Recruiting

Asan Medical Center

Seoul, South Korea

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Status: Recruiting

National Cancer Center

Seoul, South Korea

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Status: Not yet recruiting

Samsung Medical Center

Seoul, South Korea

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Status: Recruiting

Severance Hospital Yonsei University

Seoul, South Korea

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Status: Recruiting

START MADRID_Hospital Universitario HM Sanchinarro - CIOCC

Madrid, Madrid, Spain

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START MADRID_Hospital Universitario Fundacion Jimenez Diaz

Madrid, Madrid, Spain

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Status: Recruiting

NEXT Oncology-Hospital Quironsalud Barcelona

Barcelona, Spain

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Status: Recruiting

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

Barcelona, Spain

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Status: Recruiting

Hospital Clinico Universitario de Valencia

Valencia, Spain

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Status: Recruiting

START Rioja

Rioja, Spain

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Status: Not yet recruiting

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

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Sarah Cannon Research Institute UK

London, Middlesex, United Kingdom

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Status: Recruiting

Freeman Hospital

Newcastle upon Tyne, Tyne and Wear, United Kingdom

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Status: Recruiting

University of San Francisco

San Francisco, California, 94143, United States

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Status: Withdrawn

Hoag Cancer Center

Irvine, California, 92618, United States

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Status: Withdrawn

University of California Irvine Chao Family Comprehensive Cancer Center

Irvine, California, 92868, United States

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Status: Not yet recruiting

UCLA Jonsson Comprehensive Cancer Center

Los Angeles, California, 90024, United States

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USC Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

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Rocky Mountain Cancer Center

Denver, Colorado, 80218, United States

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Yale Cancer Center

New Haven, Connecticut, 06519, United States

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Medical Oncology Hematology Consultants

Newark, Delaware, 19713, United States

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Florida Cancer Specialists South

Port Charlotte, Florida, 33980, United States

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Status: Recruiting

Advent Health

Orlando, Florida, 32803, United States

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Status: Not yet recruiting

University of Miami - Sylvester Comprehensive Cancer Center

Miami, Florida, 33136, United States

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Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Chicago, Illinois, 60611, United States

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Status: Not yet recruiting

Indiana University

Indianapolis, Indiana, 46240, United States

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Status: Withdrawn

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

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Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

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Status: Recruiting

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

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Status: Recruiting

New York University - Long Island Hospital

Mineola, New York, 11501, United States

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Status: Withdrawn

New York University Perlmutter Cancer Center

New York, New York, 10016, United States

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Status: Withdrawn

Memorial Sloan Kettering

New York, New York, 10065, United States

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Status: Recruiting

Duke University

Durham, North Carolina, 27705, United States

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Status: Recruiting

The Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio, 44195, United States

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Status: Recruiting

University of Oklahoma

Oklahoma City, Oklahoma, 73104, United States

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Oregon Health & Science University (OHSU)

Portland, Oregon, 97210, United States

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Status: Recruiting

WellSpan York Cancer Center

York, Pennsylvania, 17403, United States

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Status: Not yet recruiting

Abramson Cancer Center of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

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Status: Recruiting

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

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Status: Not yet recruiting

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

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Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

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Vanderbilt University Medical Center - Ingram Cancer Center

Nashville, Tennessee, 37232, United States

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Status: Withdrawn

New Experimental Therapeutics of San Antonio - NEXT Oncology

San Antonio, Texas, 78229, United States

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Status: Recruiting

New Experimental Therapeutics - NEXT Oncology

Austin, Texas, 78705, United States

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Status: Recruiting

UTSW - Moody Outpatient Center - Parkland Health

Dallas, Texas, 75235, United States

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Status: Not yet recruiting

UT Southwest Simmons Cancer Center

Dallas, Texas, 75390, United States

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The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

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Status: Recruiting

Virginia Cancer Specialists

Fairfax, Virginia, 22031, United States

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Status: Recruiting

University of Washington, Fred Hutchinson Cancer Center

Seattle, Washington, 98109, United States

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Status: Recruiting

Swedish Medical Center

Seattle, Washington, 98122-, United States

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Status: Not yet 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)

Overview

Mechanism of action

Efficacy

Safety

Further reading

HealthScout AI Analysis

Eligibility

Show Criteria

Sites (82)

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

Asklepios Klinik Altona

Universitätsklinikum Frankfurt

Universitätsklinikum Essen

Istituti Fisioterapici Ospitalieri - Istituto Nazionale Tumori Regina Elena

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Istituto Clinico Humanitas

Istituto Europeo Di Oncologia

Fondazione IRCCS Istituto Nazionale Dei Tumori

ASST Grande Ospedale Metropolitano Niguarda

Fondazione del Piemonte per l'Oncologia (IRCCS)

IRCCS - lstituto Nazionale Tumori - Fondazione G. Pascale

Humanitas San Pio X

National Cancer Center of Singapore

National University Hospital

Seoul University Hospital

Asan Medical Center

National Cancer Center

Samsung Medical Center

Severance Hospital Yonsei University

START MADRID_Hospital Universitario HM Sanchinarro - CIOCC

START MADRID_Hospital Universitario Fundacion Jimenez Diaz

NEXT Oncology-Hospital Quironsalud Barcelona

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

Hospital Clinico Universitario de Valencia

START Rioja

Hospital Universitario 12 de Octubre

Sarah Cannon Research Institute UK

Freeman Hospital

University of San Francisco

Hoag Cancer Center

University of California Irvine Chao Family Comprehensive Cancer Center

UCLA Jonsson Comprehensive Cancer Center

USC Norris Comprehensive Cancer Center

Rocky Mountain Cancer Center

Yale Cancer Center

Medical Oncology Hematology Consultants

Florida Cancer Specialists South

Advent Health

University of Miami - Sylvester Comprehensive Cancer Center

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