The Evaluation of PC14586 in Patients With Advanced Solid Tumors Harboring a TP53 Y220C Mutation (PYNNACLE)
NCT ID: NCT04585750
Last Updated: 2025-10-31
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE1/PHASE2
300 participants
INTERVENTIONAL
2020-10-29
2027-12-31
Brief Summary
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Detailed Description
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The primary objective of Phase 2 Monotherapy is to evaluate the efficacy of rezatapopt at the Recommended Phase 2 Dose (RP2D) including the Overall Response Rate (ORR) in the Ovarian Cancer Cohort and the ORR across all cohorts as determined by blinded independent central review. Secondary objectives of Phase 2 are to characterize the safety, pharmacokinetic (PK) properties, quality of life, and other efficacy measures of PC14586 rezatapopt at the RP2D. Enrollment is open for the Phase 2 Monotherapy portion of the study.
The primary objective of Phase 1 Monotherapy is to establish the maximum tolerated dose (MTD) and RP2D of rezatapopt. Secondary objectives are to characterize the PK properties, safety and tolerability, and to assess preliminary efficacy including ORR. Enrollment into Phase 1 Monotherapy is complete.
The primary objective of Phase 1b Combination Therapy is to establish the MTD/RP2D of rezatapopt when administered in combination with pembrolizumab. Secondary objectives of Phase 1b Combination Therapy are to characterize PK, safety and tolerability, and to assess preliminary efficacy of rezatapopt when administered in combination with pembrolizumab, including ORR. Enrollment into Phase 1b Combination Therapy is complete.
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
During Phase 1 Monotherapy (Dose Escalation), participants will be assigned a dose level using an accelerated titration design in the initial dose cohorts, followed by a modified toxicity probability interval (mTPI) design in subsequent dose cohorts. Enrollment closed.
During Part 1 of the Ph 1b Combination Therapy, patients will be assigned a dose level using mTPI design. A recommended rezatapopt Phase 2 Dose (RP2D) when administered in combination with pembrolizumab will be selected at the end of Phase 1b Part 1, and the RP2D will be assigned to all participants in Part 2. Enrollment closed.
TREATMENT
NONE
Study Groups
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Phase 1 Monotherapy Dose Escalation
Multiple dose levels of daily oral rezatapopt will be evaluated in an escalating manner, to determine the maximum tolerated dose and to ensure sufficient safety experience, pharmacokinetic information, and early evidence of clinical activity of rezatapopt to recommend a Phase 2 dose (RP2D).
rezatapopt
First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.
Phase 1b Combination Therapy Dose Escalation, Part 1
Multiple dose levels of daily oral rezatapopt in combination with a stable dose of pembrolizumab (200 mg IV q3 weeks) will be evaluated in an escalating manner, to determine the maximum tolerated dose and to ensure sufficient safety experience, pharmacokinetic information, and early evidence of clinical activity of PC14586 to recommend a Phase 2 dose (RP2D) of rezatapopt when administered in combination with pembrolizumab.
rezatapopt
First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.
pembrolizumab
Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.
Phase 1b Combination Therapy Dose Expansion, PD(L)-1 naive patients
Additional (expansion of) participants will enroll at the RP2D of daily oral PC14586 (INN: rezatapopt) when administered in combination with pembrolizumab (200 mg IV q3 weeks) for continued evaluation. Participants will have advanced solid tumors harboring a p53 Y220C mutation and are PD(L)-1 naive patients.
rezatapopt
First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.
pembrolizumab
Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.
Phase 1b Combination Therapy Dose Expansion, PD(L)-1 relapsed/refractory patients
Additional (expansion of) participants will enroll at the RP2D of daily oral rezatapopt when administered in combination with pembrolizumab (200 mg IV q3 weeks) for continued evaluation. Participants will have advanced solid tumors harboring a p53 Y220C mutation and are PD(L)-1 relapsed/refractory patients.
rezatapopt
First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.
pembrolizumab
Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.
Phase 2 Monotherapy Dose Expansion, Ovarian Cancer Cohort
Additional (expansion of) participants will dose with 2000 mg daily oral PC14586 (INN: rezatapopt) with food for continued evaluation. Ovarian Cancer Cohort participants will have locally advanced or metastatic ovarian cancer harboring a TP53 Y220C mutation who meet all eligibility criteria and have measurable disease per RECIST 1.1.
rezatapopt
First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.
Phase 2 Monotherapy Dose Expansion, Lung Cancer Cohort
Additional (expansion of) participants will dose with 2000 mg daily oral PC14586 (INN: rezatapopt) with food for continued evaluation. Lung Cancer Cohort participants will have locally advanced or metastatic lung cancer harboring a TP53 Y220C mutation who meet all eligibility criteria and have measurable disease per RECIST 1.1.
rezatapopt
First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.
Phase 2 Monotherapy Dose Expansion, Breast Cancer Cohort
Additional (expansion of) participants will dose with 2000 mg daily oral PC14586 (INN: rezatapopt) with food for continued evaluation. Breast Cancer Cohort participants will have locally advanced or metastatic breast cancer harboring a TP53 Y220C mutation who meet all eligibility criteria and have measurable disease per RECIST 1.1.
rezatapopt
First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.
Phase 2 Monotherapy Dose Expansion, Endometrial Cancer Cohort
Additional (expansion of) participants will dose with 2000 mg daily oral PC14586 (INN: rezatapopt) with food for continued evaluation. Endometrial Cancer Cohort participants will have locally advanced or metastatic endometrial cancer harboring a TP53 Y220C mutation who meet all eligibility criteria and have measurable disease per RECIST 1.1.
rezatapopt
First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.
Phase 2 Monotherapy Dose Expansion, Other Solid Tumors Cohort
Additional (expansion of) participants will dose with 2000 mg daily oral PC14586 (INN: rezatapopt) with food for continued evaluation. Other Solid Tumors Cohort participants will have locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation who meet all eligibility criteria and have measurable disease per RECIST 1.1.
rezatapopt
First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.
Interventions
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rezatapopt
First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.
pembrolizumab
Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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
12 Years
ALL
No
Sponsors
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Merck Sharp & Dohme LLC
INDUSTRY
PMV Pharmaceuticals, Inc
INDUSTRY
Responsible Party
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Principal Investigators
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Marc Fellous, MD
Role: STUDY_DIRECTOR
Sr. Vice President of Medical Affairs
Locations
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University of California Irvine Chao Family Comprehensive Cancer Center
Irvine, California, United States
UCLA Jonsson Comprehensive Cancer Center
Los Angeles, California, United States
USC Norris Comprehensive Cancer Center
Los Angeles, California, United States
Rocky Mountain Cancer Center
Denver, Colorado, United States
Yale Cancer Center
New Haven, Connecticut, United States
Medical Oncology Hematology Consultants
Newark, Delaware, United States
University of Miami - Sylvester Comprehensive Cancer Center
Miami, Florida, United States
Advent Health
Orlando, Florida, United States
Florida Cancer Specialists South
Port Charlotte, Florida, United States
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Chicago, Illinois, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Dana Farber Cancer Institute
Boston, Massachusetts, United States
Karmanos Cancer Institute
Detroit, Michigan, United States
Memorial Sloan Kettering
New York, New York, United States
Duke University
Durham, North Carolina, United States
The Cleveland Clinic Taussig Cancer Center
Cleveland, Ohio, United States
University of Oklahoma
Oklahoma City, Oklahoma, United States
Oregon Health & Science University (OHSU)
Portland, Oregon, United States
Abramson Cancer Center of the University of Pennsylvania
Philadelphia, Pennsylvania, United States
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States
WellSpan York Cancer Center
York, Pennsylvania, United States
Medical University of South Carolina
Charleston, South Carolina, United States
Sarah Cannon Research Institute
Nashville, Tennessee, United States
New Experimental Therapeutics - NEXT Oncology
Austin, Texas, United States
UTSW - Moody Outpatient Center - Parkland Health
Dallas, Texas, United States
UT Southwest Simmons Cancer Center
Dallas, Texas, United States
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
New Experimental Therapeutics of San Antonio - NEXT Oncology
San Antonio, Texas, United States
Virginia Cancer Specialists
Fairfax, Virginia, United States
University of Washington, Fred Hutchinson Cancer Center
Seattle, Washington, United States
University of Wisconsin Carbone Cancer Center
Madison, Wisconsin, United States
Chris O'Brien Lifehouse Hospital
Camperdown, New South Wales, Australia
Mater Cancer Care Centre
South Brisbane, Queensland, Australia
Flinders Medical Center
Bedford Park, South Australia, Australia
Monash Medical Centre
Clayton, Victoria, Australia
Linear Clinical Research
Nedlands, Western Australia, Australia
ICANS - Institut de cancérologie Strasbourg Europe
Strasbourg, Bas-Rhin, France
Institut Bergonie
Bordeaux, Gironde, France
Institut Claudius Regaud
Toulouse, Haute-Garonne, France
EDOG Institut de Cancerologie de l'Ouest
Saint-Herblain, Loire-Atlantique, France
Centre Jean Perrin
Clermont-Ferrand, Puy-de-Dôme, France
Institut Gustave Roussy
Villejuif, Val-de-Marne, France
Centre Léon Bérard Centre Régional de Lutte Contre Le Cancer
Lyon, , France
CHU de Nîmes
Nîmes, , France
Institute Cancer De Lorraine
Vandœuvre-lès-Nancy, , France
Nationale Centrum für Tumorerkrankungen (NCT) Heidelberg
Heidelberg, Baden-Wurttemberg, Germany
Universitätsklinikum Augsburg
Augsburg, Bavaria, Germany
Asklepios Klinik Altona
Hamburg, City state of Hamburg, Germany
Universitätsklinikum Frankfurt
Frankfurt am Main, Hesse, Germany
Universitätsklinikum Essen
Essen, North Rhine-Westphalia, Germany
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Rome, Lazio, Italy
Istituti Fisioterapici Ospitalieri - Istituto Nazionale Tumori Regina Elena
Rome, Lazio, Italy
ASST Grande Ospedale Metropolitano Niguarda
Milan, Lombardy, Italy
Fondazione IRCCS Istituto Nazionale Dei Tumori
Milan, Lombardy, Italy
Istituto Europeo Di Oncologia
Milan, Lombardy, Italy
Istituto Clinico Humanitas
Rozzano, Lombardy, Italy
Fondazione del Piemonte per l'Oncologia (IRCCS)
Candiolo, Torino, Italy
Humanitas San Pio X
Milan, , Italy
IRCCS - lstituto Nazionale Tumori - Fondazione G. Pascale
Napoli, , Italy
National University Hospital
Kent Ridge, , Singapore
National Cancer Center of Singapore
Singapore, , Singapore
Asan Medical Center
Seoul, , South Korea
National Cancer Center
Seoul, , South Korea
Samsung Medical Center
Seoul, , South Korea
Seoul University Hospital
Seoul, , South Korea
Severance Hospital Yonsei University
Seoul, , South Korea
START MADRID_Hospital Universitario Fundacion Jimenez Diaz
Madrid, Madrid, Spain
START MADRID_Hospital Universitario HM Sanchinarro - CIOCC
Madrid, Madrid, Spain
Instituto de Investigacion Oncologica Vall d'Hebron (VHIO) - EPON
Barcelona, , Spain
NEXT Oncology-Hospital Quironsalud Barcelona
Barcelona, , Spain
Hospital Universitario 12 de Octubre
Madrid, , Spain
START Rioja
Rioja, , Spain
Hospital Clinico Universitario de Valencia
Valencia, , Spain
Sarah Cannon Research Institute UK
London, Middlesex, United Kingdom
Freeman Hospital
Newcastle upon Tyne, Tyne and Wear, United Kingdom
Countries
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Central Contacts
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Facility Contacts
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Zhaohui Arter, MD
Role: primary
Gottfried Konecny, MD
Role: primary
Anthony El-Khoueiry, MD
Role: primary
Allen Cohn, MD
Role: primary
Patricia LoRusso, MD
Role: primary
Jamal Misleh, MD
Role: primary
Gilberto de Lima Lopes Jr., MD
Role: primary
Guru Sonpavde, MD
Role: primary
Ivor Percent, MD
Role: primary
Devalingam Mahalingam, MD, PhD
Role: primary
Aparna Parikh, MD
Role: primary
Geoffrey Shapiro, MD, PhD
Role: primary
Dipesh Uprety, MD
Role: primary
Alison Schram, MD
Role: primary
Niharika Mettu, MD, PhD
Role: primary
Dale Shepard, MD
Role: primary
Debra Richardson, MD
Role: primary
Shivaani Kummar, MD
Role: primary
Lainie Martin, MD
Role: primary
Sarah Taylor, MD, PhD
Role: primary
Ikechukwu Akunyili, MD
Role: primary
John Kaczmar, MD
Role: primary
Melissa Johnson, MD
Role: primary
Anthony Tolcher, MD
Role: primary
David Miller, MD
Role: primary
David Miller, MD
Role: primary
Ecaterina Dumbrava, MD
Role: primary
Anthony Tolcher, MD
Role: primary
Alexander Spira, MD
Role: primary
Andrew Coveler, MD
Role: primary
Nataliya Uboha, MD, PhD
Role: primary
Peter Grimison, MD
Role: primary
Catherine Shannon, MD
Role: primary
Shwagi Sukumaran, MD
Role: primary
Amy Body, MD
Role: primary
Michael Millward, MD
Role: primary
Lauriane Eberst, MD
Role: primary
Antoine Italiano, MD
Role: primary
Carlos-Alberto Gomez-Roca, MD
Role: primary
Jean-Sebastien Frenel, MD
Role: primary
Xavier Durando, MD
Role: primary
Yohann Loriot, MD
Role: primary
Isabelle Ray-Coquard, MD
Role: primary
Frédéric Fiteni, MD, PhD
Role: primary
Aurélien Lambert, MD
Role: primary
Martin Haag, MD
Role: primary
Rainer Claus, MD
Role: primary
Dirk Arnold, MD
Role: primary
Martin Sebastian, MD
Role: primary
Marcel Wiesweg, MD
Role: primary
Giovanni Scambia, MD
Role: primary
Lorenza Landi, MD
Role: primary
Salvatore Siena, MD
Role: primary
Massimo Di Nicola, MD
Role: primary
Giuseppe Curigliano, MD
Role: primary
Armando Santoro, MD
Role: primary
Chiara Lazzari, MD
Role: primary
Domenica Lorusso, MD
Role: primary
Anna Passarelli, MD
Role: primary
David Shao Peng Tan, MD
Role: primary
Tira Tan, MD
Role: primary
Dae Ho Lee, MD
Role: primary
Myong Cheol Lim, MD, PhD
Role: primary
Byoung Gie Kim, MD
Role: primary
Seock-Ah Im, MD
Role: primary
Jung-Yun Lee, MD
Role: primary
Victor Moreno Garcia, MD
Role: primary
Maria Jose De Miguel Luken, MD
Role: primary
Irene Braña, MD
Role: primary
Elena Garralda, MD
Role: primary
Santiago Ponce Aix, MD
Role: primary
Maria de Miguel Luken, MD
Role: primary
Desamparados Roda Perez, MD
Role: primary
Elisa Fontana, MD, PhD
Role: primary
Alastair Greystoke, MB ChB PhD
Role: primary
References
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Schram AM, Fellous M, LeDuke K, Schmid A, Dumbrava EE. PYNNACLE phase II clinical trial protocol: rezatapopt (PC14586) monotherapy in advanced or metastatic solid tumors with a TP53 Y220C mutation. Future Oncol. 2025 Sep 11:1-8. doi: 10.1080/14796694.2025.2557176. Online ahead of print.
Papavassiliou KA, Vassiliou AG, Papavassiliou AG. Rezatapopt: A promising small-molecule "refolder" specific for TP53Y220C mutant tumors. Neoplasia. 2025 Sep;67:101201. doi: 10.1016/j.neo.2025.101201. Epub 2025 Jun 20.
Other Identifiers
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KEYNOTE-D79
Identifier Type: REGISTRY
Identifier Source: secondary_id
MK-3475-D79
Identifier Type: REGISTRY
Identifier Source: secondary_id
PMV-586-101
Identifier Type: -
Identifier Source: org_study_id
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