The Evaluation of PC14586 in Patients With Advanced Solid Tumors Harboring a TP53 Y220C Mutation (PYNNACLE)
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)
3 other identifiers
interventional
300
9 countries
76
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Oct 2020
Longer than P75 for phase_1
76 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
October 1, 2020
CompletedFirst Posted
Study publicly available on registry
October 14, 2020
CompletedStudy Start
First participant enrolled
October 29, 2020
CompletedPrimary Completion
Last participant's last visit for primary outcome
August 15, 2026
ExpectedStudy Completion
Last participant's last visit for all outcomes
December 31, 2027
March 12, 2026
March 1, 2026
5.8 years
October 1, 2020
March 10, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (9)
Phase 1 Monotherapy (Dose Escalation): Determine the number and type of adverse events to characterize the safety of rezatapopt
Number of participants with treatment related adverse events
40 months
Phase 1 Monotherapy (Dose Escalation): Establish the Recommended Phase 2 Dose (RP2D)
RP2D will be determined using available safety and pharmacokinetics and pharmacodynamics data
30 months
Phase 1 Monotherapy (Dose Escalation): Establish the maximum tolerated dose (MTD) (Phase 1)
Incidence of dose limiting toxicities (DLTs) during the first 28 days of treatment with rezatapopt
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
Number of participants with treatment related adverse events
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
Incidence of dose limiting toxicities (DLTs) during the first 28 days of treatment with rezatapopt
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
RP2D will be determined using available safety and pharmacokinetics and pharmacodynamics data
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
Number of participants with treatment related adverse events
12 months for treatment arm
Phase 2 Monotherapy (Dose Expansion): Response rate assessment to evaluate the clinical activity / efficacy of rezatapopt
Overall response rate in accordance with Response Evaluation Criteria (RECIST) v.1.1 as assessed by independent review across all cohorts
34 months
Phase 2 Monotherapy (Dose Expansion): Response rate assessment to evaluate the clinical activity / efficacy of rezatapopt in ovarian cancer patients
Overall response rate in accordance with Response Evaluation Criteria (RECIST) v.1.1 as assessed by independent review in the ovarian cancer cohort
34 months
Secondary Outcomes (45)
Phase 1 Monotherapy: PK profile of rezatapopt - Peak concentration (Cmax)
Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 1 Monotherapy: PK profile of rezatapopt - Time of peak concentration (Tmax)
Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 1 Monotherapy: PK profile of rezatapopt - Area under the plasma concentration-time curve from time zero to time of last sampling timepoint (AUC0-t)
Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 1 Monotherapy: PK profile of rezatapopt - Area under the plasma concentration-time curve in one dosing interval (AUCtau)
Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 1 Monotherapy: PK profile of rezatapopt - Trough observed concentrations (Ctrough/Ctau)
Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
- +40 more secondary outcomes
Study Arms (9)
Phase 1 Monotherapy Dose Escalation
EXPERIMENTALMultiple 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).
Phase 1b Combination Therapy Dose Escalation, Part 1
EXPERIMENTALMultiple 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.
Phase 1b Combination Therapy Dose Expansion, PD(L)-1 naive patients
EXPERIMENTALAdditional (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.
Phase 1b Combination Therapy Dose Expansion, PD(L)-1 relapsed/refractory patients
EXPERIMENTALAdditional (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.
Phase 2 Monotherapy Dose Expansion, Ovarian Cancer Cohort
EXPERIMENTALAdditional (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.
Phase 2 Monotherapy Dose Expansion, Lung Cancer Cohort
EXPERIMENTALAdditional (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.
Phase 2 Monotherapy Dose Expansion, Breast Cancer Cohort
EXPERIMENTALAdditional (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.
Phase 2 Monotherapy Dose Expansion, Endometrial Cancer Cohort
EXPERIMENTALAdditional (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.
Phase 2 Monotherapy Dose Expansion, Other Solid Tumors Cohort
EXPERIMENTALAdditional (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.
Interventions
Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.
First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.
Eligibility Criteria
You may qualify if:
- 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)
- Anti-PD-1/PD-L1 naive or must have progressed on treatment
- Measurable disease
You may not qualify if:
- 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
- Known KRAS mutation, defined as a single nucleotide variant (SNV) (Phase 2)
- 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
- +8 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- PMV Pharmaceuticals, Inclead
- Merck Sharp & Dohme LLCcollaborator
Study Sites (76)
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
Massachusetts General Hospital
Boston, Massachusetts, 02114, United States
Dana Farber Cancer Institute
Boston, Massachusetts, 02215, United States
Karmanos Cancer Institute
Detroit, Michigan, 48201, United States
Columbia University
New York, New York, 10032, United States
Memorial Sloan Kettering
New York, New York, 10065, United States
Duke University
Durham, North Carolina, 27705, United States
The Cleveland Clinic Taussig Cancer Center
Cleveland, Ohio, 44195, United States
University of Oklahoma
Oklahoma City, Oklahoma, 73104, United States
Oregon Health & Science University (OHSU)
Portland, Oregon, 97210, United States
Abramson Cancer Center of the University of Pennsylvania
Philadelphia, Pennsylvania, 19104, United States
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, 15213, United States
WellSpan York Cancer Center
York, Pennsylvania, 17403, United States
Medical University of South Carolina
Charleston, South Carolina, 29425, United States
Sarah Cannon Research Institute
Nashville, Tennessee, 37203, United States
New Experimental Therapeutics - NEXT Oncology
Austin, Texas, 78705, United States
UTSW - Moody Outpatient Center - Parkland Health
Dallas, Texas, 75235, United States
UT Southwest Simmons Cancer Center
Dallas, Texas, 75390, United States
The University of Texas MD Anderson Cancer Center
Houston, Texas, 77030, United States
New Experimental Therapeutics of San Antonio - NEXT Oncology
San Antonio, Texas, 78229, United States
Virginia Cancer Specialists
Fairfax, Virginia, 22031, United States
University of Washington, Fred Hutchinson Cancer Center
Seattle, Washington, 98109, United States
University of Wisconsin Carbone Cancer Center
Madison, Wisconsin, 53705, 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, 30900, France
Institute Cancer De Lorraine
Vandœuvre-lès-Nancy, 54519, France
Nationale Centrum für Tumorerkrankungen (NCT) Heidelberg
Heidelberg, Baden-Wurttemberg, Germany
Universitätsklinikum Augsburg
Augsburg, Bavaria, Germany
Asklepios Klinik Altona
Hamburg, 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
Naples, 80131, Italy
National University Hospital
Kent Ridge, Singapore
National Cancer Center of Singapore
Singapore, 168582, 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, 28041, 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
Related Publications (3)
Dumbrava EE, Shapiro GI, Parikh AR, Johnson ML, Tolcher AW, Thompson JA, El-Khoueiry AB, Vandross AL, Kummar S, Shepard DR, LeDuke K, Sheehan L, Alland L, Haque A, Jalota D, Fellous M, Schram AM. Phase 1 Study of Rezatapopt, a p53 Reactivator, in TP53 Y220C-Mutated Tumors. N Engl J Med. 2026 Feb 26;394(9):872-883. doi: 10.1056/NEJMoa2508820.
PMID: 41740031DERIVEDSchram 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 Oct;21(24):3159-3166. doi: 10.1080/14796694.2025.2557176. Epub 2025 Sep 11.
PMID: 40932470DERIVEDPapavassiliou 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.
PMID: 40543428DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Study Officials
- STUDY DIRECTOR
Marc Fellous, MD
Sr. Vice President of Medical Affairs
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
October 1, 2020
First Posted
October 14, 2020
Study Start
October 29, 2020
Primary Completion (Estimated)
August 15, 2026
Study Completion (Estimated)
December 31, 2027
Last Updated
March 12, 2026
Record last verified: 2026-03
Data Sharing
- IPD Sharing
- Will not share