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)

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.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; Head and Neck Cancer; Small Cell Lung Carcinoma; Small Cell Lung Cancer; Colorectal Cancer; Ovarian Cancer; Non-Small Cell Lung Cancer; NSCLC; Lung Cancer; Prostate Cancer; Metastatic Cancer; SCLC; Triple Negative Breast Cancer; Advanced Solid Tumor; Endometrial Cancer; Metastatic Solid Tumor; HER2-positive Breast Cancer; Gall Bladder Cancer; HER2-negative Breast Cancer; Other Cancer; Advanced Malignant Neoplasm; TNBC; Non-Small Cell Lung Carcinoma; HER2+ Breast Cancer; NSCLC (Non-small Cell Lung Cancer); Locally Advanced; Small Cell Lung Cancer ( SCLC ); ER/PR Positive Breast Cancer; ER/PR(+), Her2(-) Breast Cancer; HER2- Breast Cancer
• Intervention / Treatment: Drug: pembrolizumab; Drug: rezatapopt

Detailed Description

Rezatapopt is a first-in-class, oral, small molecule p53 reactivator that is selective for the TP53 Y220C mutation.

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.

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: PMV Pharma Clinical Study Information Center; Phone Number: (609) 235-4038; Email: clinicaltrials@pmvpharma.com

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia
      • Recruiting
      • Chris O'Brien Lifehouse Hospital
      • Contact: Peter Grimison, MD
  • Queensland
    • South Brisbane, Queensland, Australia
      • Recruiting
      • Mater Cancer Care Centre
      • Contact: Catherine Shannon, MD
  • South Australia
    • Bedford Park, South Australia, Australia
      • Recruiting
      • Flinders Medical Center
      • Contact: Shwagi Sukumaran, MD
  • Victoria
    • Clayton, Victoria, Australia
      • Recruiting
      • Monash Medical Centre
      • Contact: Amy Body, MD
  • Western Australia
    • Nedlands, Western Australia, Australia
      • Recruiting
      • Linear Clinical Research
      • Contact: Michael Millward, MD
• France
  • Lyon, France
    • Recruiting
    • Centre Léon Bérard Centre Régional de Lutte Contre Le Cancer
    • Contact: Isabelle Ray-Coquard, MD
  • Nîmes, France, 30900
    • Recruiting
    • CHU de Nîmes
    • Contact: Frédéric Fiteni, MD, PhD
  • Vandœuvre-lès-Nancy, France, 54519
    • Recruiting
    • Institute Cancer De Lorraine
    • Contact: Aurélien Lambert, MD
  • Bas-Rhin
    • Strasbourg, Bas-Rhin, France
      • Recruiting
      • ICANS - Institut de cancérologie Strasbourg Europe
      • Contact: Lauriane Eberst, MD
  • Gironde
    • Bordeaux, Gironde, France
      • Recruiting
      • Institut Bergonie
      • Contact: Antoine Italiano, MD
  • Haute-Garonne
    • Toulouse, Haute-Garonne, France
      • Recruiting
      • Institut Claudius Regaud
      • Contact: Carlos-Alberto Gomez-Roca, MD
  • Loire-Atlantique
    • Saint-Herblain, Loire-Atlantique, France
      • Recruiting
      • EDOG Institut de Cancerologie de l'Ouest
      • Contact: Jean-Sebastien Frenel, MD
  • Puy-de-Dôme
    • Clermont-Ferrand, Puy-de-Dôme, France
      • Recruiting
      • Centre Jean Perrin
      • Contact: Xavier Durando, MD
  • Val-de-Marne
    • Villejuif, Val-de-Marne, France
      • Recruiting
      • Institut Gustave Roussy
      • Contact: Yohann Loriot, MD
• Germany
  • Baden-Wurttemberg
    • Heidelberg, Baden-Wurttemberg, Germany
      • Recruiting
      • Nationale Centrum für Tumorerkrankungen (NCT) Heidelberg
      • Contact: Martin Haag, MD
  • Bavaria
    • Augsburg, Bavaria, Germany
      • Recruiting
      • Universitätsklinikum Augsburg
      • Contact: Rainer Claus, MD
  • Hamburg
    • Hamburg, Hamburg, Germany
      • Recruiting
      • Asklepios Klinik Altona
      • Contact: Dirk Arnold, MD
  • Hesse
    • Frankfurt am Main, Hesse, Germany
      • Withdrawn
      • Universitätsklinikum Frankfurt
  • North Rhine-Westphalia
    • Essen, North Rhine-Westphalia, Germany
      • Recruiting
      • Universitätsklinikum Essen
      • Contact: Marcel Wiesweg, MD
• Italy
  • Milan, Italy
    • Recruiting
    • Humanitas San Pio X
    • Contact: Domenica Lorusso, MD
  • Napoli, Italy, 80131
    • Recruiting
    • IRCCS - lstituto Nazionale Tumori - Fondazione G. Pascale
    • Contact: Anna Passarelli, MD
  • Lazio
    • Rome, Lazio, Italy
      • Recruiting
      • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
      • Contact: Anna Fagotti, MD
    • Rome, Lazio, Italy
      • Recruiting
      • Istituti Fisioterapici Ospitalieri - Istituto Nazionale Tumori Regina Elena
      • Contact: Lorenza Landi, MD
  • Lombardy
    • Milan, Lombardy, Italy
      • Recruiting
      • ASST Grande Ospedale Metropolitano Niguarda
      • Contact: Salvatore Siena, MD
    • Milan, Lombardy, Italy
      • Recruiting
      • Fondazione IRCCS Istituto Nazionale dei Tumori
      • Contact: Massimo Di Nicola, MD
    • Milan, Lombardy, Italy
      • Recruiting
      • Istituto Europeo di Oncologia
      • Contact: Giuseppe Curigliano, MD
    • Rozzano, Lombardy, Italy
      • Recruiting
      • Istituto Clinico Humanitas
      • Contact: Armando Santoro, MD
  • Torino
    • Candiolo, Torino, Italy
      • Recruiting
      • Fondazione del Piemonte per l'Oncologia (IRCCS)
      • Contact: Chiara Lazzari, MD
• Singapore
  • Kent Ridge, Singapore
    • Recruiting
    • National University Hospital
    • Contact: David Shao Peng Tan, MD
  • Singapore, Singapore, 168582
    • Recruiting
    • National Cancer Center of Singapore
    • Contact: Tira Tan, MD
• South Korea
  • Seoul, South Korea
    • Recruiting
    • Samsung Medical Center
    • Contact: Chel Hun Choi, MD
  • Seoul, South Korea
    • Recruiting
    • Asan Medical Center
    • Contact: Dae Ho Lee, MD
  • Seoul, South Korea
    • Recruiting
    • Seoul University hospital
    • Contact: Seock-Ah Im, MD
  • Seoul, South Korea
    • Recruiting
    • Severance Hospital Yonsei University
    • Contact: Jung-Yun Lee, MD
  • Seoul, South Korea
    • Recruiting
    • National Cancer Center
    • Contact: Myong Cheol Lim, MD, PhD
• Spain
  • Barcelona, Spain
    • Recruiting
    • Next Oncology-Hospital Quironsalud Barcelona
    • Contact: Elena Garralda, MD
  • Barcelona, Spain
    • Recruiting
    • Instituto de Investigacion Oncologica Vall d'Hebron (VHIO) - EPON
    • Contact: Lorena Farinas, MD
  • Madrid, Spain, 28041
    • Recruiting
    • Hospital Universitario 12 De Octubre
    • Contact: Santiago Ponce Aix, MD
  • Rioja, Spain
    • Recruiting
    • START Rioja
    • Contact: Maria de Miguel Luken, MD
  • Valencia, Spain
    • Recruiting
    • Hospital Clinico Universitario de Valencia
    • Contact: José Alejandro Pérez Fidalgo, MD
  • Madrid
    • Madrid, Madrid, Spain
      • Recruiting
      • START MADRID_Hospital Universitario Fundacion Jimenez Diaz
      • Contact: Victor Moreno Garcia, MD
    • Madrid, Madrid, Spain
      • Recruiting
      • START MADRID_Hospital Universitario HM Sanchinarro - CIOCC
      • Contact: Irene Moreno, MD
• United Kingdom
  • Middlesex
    • London, Middlesex, United Kingdom
      • Recruiting
      • Sarah Cannon Research Institute UK
      • Contact: Elisa Fontana, MD, PhD
  • Tyne and Wear
    • Newcastle upon Tyne, Tyne and Wear, United Kingdom
      • Recruiting
      • Freeman Hospital
      • Contact: Alastair Greystoke, MB ChB PhD
• United States
  • California
    • Irvine, California, United States, 92868
      • Recruiting
      • University of California Irvine Chao Family Comprehensive Cancer Center
      • Contact: Zhaohui Arter, MD
    • La Jolla, California, United States, 92093
      • Not yet recruiting
      • University of San Diego Moores Cancer Center
      • Contact: Shumei Kato, MD
    • Los Angeles, California, United States, 90033
      • Recruiting
      • Usc Norris Comprehensive Cancer Center
      • Contact: Anthony El-Khoueiry, MD
    • Los Angeles, California, United States, 90024
      • Recruiting
      • UCLA Jonsson Comprehensive Cancer Center
      • Contact: Gottfried Konecny, MD
  • Colorado
    • Denver, Colorado, United States, 80218
      • Recruiting
      • Rocky Mountain Cancer Center
      • Contact: Allen Cohn, MD
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Recruiting
      • Yale Cancer Center
      • Contact: Patricia LoRusso, MD
  • Delaware
    • Newark, Delaware, United States, 19713
      • Recruiting
      • Medical Oncology Hematology Consultants
      • Contact: Jamal Misleh, MD
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami - Sylvester Comprehensive Cancer Center
      • Contact: Gilberto de Lima Lopes Jr., MD
    • Orlando, Florida, United States, 32803
      • Not yet recruiting
      • Advent Health
      • Contact: Robert Holloway, MD
    • Port Charlotte, Florida, United States, 33980
      • Recruiting
      • Florida Cancer Specialists South
      • Contact: Ivor Percent, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Aparna Parikh, MD
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana Farber Cancer Institute
      • Contact: Geoffrey Shapiro, MD, PhD
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Recruiting
      • Karmanos Cancer Institute
      • Contact: Dipesh Uprety, MD
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering
      • Contact: Alison Schram, MD
    • New York, New York, United States, 10032
      • Not yet recruiting
      • Columbia University
      • Contact: June Hou, MD
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Recruiting
      • Duke University
      • Contact: Niharika Mettu, MD, PhD
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • The Cleveland Clinic Taussig Cancer Center
      • Contact: Dale Shepard, MD
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • University of Oklahoma
      • Contact: Debra Richardson, MD
  • Oregon
    • Portland, Oregon, United States, 97210
      • Recruiting
      • Oregon Health & Science University (OHSU)
      • Contact: Shivaani Kummar, MD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Abramson Cancer Center of The University of Pennsylvania
      • Contact: Lainie Martin, MD
    • Pittsburgh, Pennsylvania, United States, 15213
      • Not yet recruiting
      • University of Pittsburgh Medical Center
      • Contact: Sarah Taylor, MD, PhD
    • York, Pennsylvania, United States, 17403
      • Recruiting
      • WellSpan York Cancer Center
      • Contact: Ikechukwu Akunyili, MD
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Terminated
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • Sarah Cannon Research Institute
      • Contact: Melissa Johnson, MD
  • Texas
    • Austin, Texas, United States, 78705
      • Recruiting
      • New Experimental Therapeutics - NEXT Oncology
      • Contact: Anthony Tolcher, MD
    • Dallas, Texas, United States, 75235
      • Not yet recruiting
      • UTSW - Moody Outpatient Center - Parkland Health
      • Contact: David Miller, MD
    • Dallas, Texas, United States, 75390
      • Recruiting
      • UT Southwest Simmons Cancer Center
      • Contact: David Miller, MD
    • Houston, Texas, United States, 77030
      • Recruiting
      • The University of Texas MD Anderson Cancer Center
      • Contact: Ecaterina Dumbrava, MD
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • New Experimental Therapeutics of San Antonio - NEXT Oncology
      • Contact: Anthony Tolcher, MD
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • Virginia Cancer Specialists
      • Contact: Alexander Spira, MD
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • University of Washington, Fred Hutchinson Cancer Center
      • Contact: Andrew Coveler, MD
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • Recruiting
      • University of Wisconsin Carbone Cancer Center
      • Contact: Nataliya Uboha, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: pembrolizumab; Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.; Other Names: MK-3475; KEYTRUDA®; KEYNOTE-D79; MK-3475-D79; Drug: rezatapopt; First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.; Other Names: PC14586
Experimental: 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.	Drug: rezatapopt; First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.; Other Names: PC14586
Experimental: 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.	Drug: rezatapopt; First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.; Other Names: PC14586
Experimental: 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.	Drug: rezatapopt; First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.; Other Names: PC14586
Experimental: 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.	Drug: rezatapopt; First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.; Other Names: PC14586
Experimental: 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.	Drug: rezatapopt; First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.; Other Names: PC14586
Experimental: 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).	Drug: rezatapopt; First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.; Other Names: PC14586
Experimental: 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.	Drug: pembrolizumab; Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.; Other Names: MK-3475; KEYTRUDA®; KEYNOTE-D79; MK-3475-D79; Drug: rezatapopt; First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.; Other Names: PC14586
Experimental: 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.	Drug: pembrolizumab; Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.; Other Names: MK-3475; KEYTRUDA®; KEYNOTE-D79; MK-3475-D79; Drug: rezatapopt; First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.; Other Names: PC14586

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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): 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 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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 2 Monotherapy (Dose Expansion): Quality of life assessment	Changes from baseline in quality of life as measured by a validated instrument, for participants 18 and older	Evaluated at every visit. 34 months for treatment arm (end of Phase 2)
Phase 1 Monotherapy: PK profile of rezatapopt - Peak concentration (Cmax)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt	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)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt	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)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt	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)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt	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)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt	Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 1 Monotherapy (Dose Escalation): Overall Response Rate per RECIST v1.1 or PCWG3 modified RECIST v1.1	Evaluation of preliminary anti-tumor activity of rezatapopt as a single agent	41 months for study (end of Phase 1)
Phase 1 Monotherapy (Dose Escalation): Time to Response per RECIST v1.1 or PCWG3 modified RECIST v1.1	Evaluation of preliminary anti-tumor activity of rezatapopt as a single agent	41 months for study (end of Phase 1)
Phase 1 Monotherapy (Dose Escalation): Duration of Response per RECIST v1.1 or PCWG3 modified RECIST v1.1	Evaluation of preliminary anti-tumor activity of rezatapopt as a single agent	41 months for study (end of Phase 1)
Phase 1 Monotherapy (Dose Escalation): Disease Control Rate per RECIST v1.1 or PCWG3 modified RECIST v1.1	Evaluation of preliminary anti-tumor activity of rezatapopt as a single agent	41 months for study (end of Phase 1)
Phase 1 Monotherapy (Dose Escalation): Progression Free Survival per RECIST v1.1 or PCWG3 modified RECIST v1.1	Evaluation of preliminary anti-tumor activity of rezatapopt as a single agent	41 months for study (end of Phase 1)
Phase 1 Monotherapy (Dose Escalation): Overall Survival	Evaluation of preliminary anti-tumor activity of rezatapopt as a single agent	41 months for study (end of Phase 1)
Phase 1b Combination Therapy: PK profile of rezatapopt in combination with pembrolizumab - Peak concentration (Cmax)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt	Approximately 12 months per patient (30 months for treatment arm)
Phase 1b Combination Therapy: PK profile of rezatapopt in combination with pembrolizumab - Time of peak concentration (Tmax)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt	Approximately 12 months per patient (30 months for treatment arm)
Phase 1b Combination Therapy: PK profile of rezatapopt in combination with pembrolizumab - Area under the plasma concentration-time curve from time zero to time of last sampling timepoint (AUC0-t)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt	Approximately 12 months per patient (30 months for treatment arm)
Phase 1b Combination Therapy: PK profile of rezatapopt in combination with pembrolizumab - Area under the plasma concentration-time curve in one dosing interval (AUCtau)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt	Approximately 12 months per patient (30 months for treatment arm)
Phase 1b Combination Therapy: PK profile of rezatapopt in combination with pembrolizumab - Trough observed concentrations (Ctrough/Ctau)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt	Approximately 12 months per patient (30 months for treatment arm)
Phase 1b Combination Therapy: Overall Response Rate per RECIST v1.1, iRECIST, or PCWG3 as assessed by Investigator and as assessed by independent review	Evaluation of anti-tumor activity of rezatapopt in combination with pembrolizumab	30 months for study (end of Phase 1b)
Phase 1b Combination Therapy: Time to Response per RECIST v1.1, iRECIST, or PCWG3 as assessed by Investigator and as assessed by independent review	Evaluation of anti-tumor activity of rezatapopt in combination with pembrolizumab	30 months for study (end of Phase 1b)
Phase 1b Combination Therapy: Duration of Response per RECIST v1.1, iRECIST, or PCWG3 as assessed by Investigator and as assessed by independent review	Evaluation of anti-tumor activity of rezatapopt in combination with pembrolizumab	30 months for study (end of Phase 1b)
Phase 1b Combination Therapy: Disease Control Rate per RECIST v1.1, iRECIST, or PCWG3 as assessed by Investigator and as assessed by independent review	Evaluation of anti-tumor activity of rezatapopt in combination with pembrolizumab	30 months for study (end of Phase 1b)
Phase 1b Combination Therapy: Overall Survival	Evaluation of anti-tumor activity of rezatapopt in combination with pembrolizumab	30 months for study (end of Phase 1b)
Phase 1b Combination Therapy: Determine the number and type of adverse events to characterize the safety of rezatapopt	Number of participants with treatment related adverse events	30 months for study (end of Phase 1b)
Phase 1b Combination Therapy: Progression Free Survival per RECIST v1.1, iRECIST, or PCWG3 as assessed by Investigator and as assessed by independent review	Evaluation of anti-tumor activity of rezatapopt in combination with pembrolizumab	30 months for study (end of Phase 1b)
Phase 2 Monotherapy: PK profile of rezatapopt - Time of peak concentration (Tmax)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt	Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 2 Monotherapy: PK profile of rezatapopt - Peak concentration (Cmax)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt	Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 2 Monotherapy: PK profile of rezatapopt - Area under the plasma concentration-time curve from time zero to time of last sampling timepoint (AUC0-t)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt	Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 2 Monotherapy: PK profile of rezatapopt - Area under the plasma concentration-time curve in one dosing interval (AUCtau)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt	Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 2 Monotherapy: PK profile of rezatapopt - Trough observed concentrations (Ctrough/Ctau)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt	Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 2 Monotherapy (Dose Expansion): Determine the number and type of adverse events to characterize the safety of rezatapopt	Number of participants with treatment related adverse events	34 months for study (end of Phase 2)
Phase 2 Monotherapy (Dose Expansion): Overall Response Rate across all cohorts per RECIST v1.1 as assessed by Investigator	Evaluation of anti-tumor activity of rezatapopt as a single agent	34 months for study (end of Phase 2)
Phase 2 Monotherapy (Dose Expansion): Overall Response Rate in ovarian cancer cohort per RECIST v1.1 as assessed by Investigator	Evaluation of anti-tumor activity of rezatapopt as a single agent	34 months for study (end of Phase 2)
Phase 2 Monotherapy (Dose Expansion): Time to Response in ovarian cancer cohort per RECIST v1.1 as assessed by Investigator and as assessed by independent review	Evaluation of anti-tumor activity of rezatapopt as a single agent	34 months for study (end of Phase 2)
Phase 2 Monotherapy (Dose Expansion): Time to Response across all cohorts per RECIST v1.1 as assessed by Investigator and as assessed by independent review	Evaluation of anti-tumor activity of rezatapopt as a single agent	34 months for study (end of Phase 2)
Phase 2 Monotherapy (Dose Expansion): Duration of Response in ovarian cancer cohort per RECIST v1.1 as assessed by Investigator and as assessed by independent review	Evaluation of anti-tumor activity of rezatapopt as a single agent	34 months for study (end of Phase 2)
Phase 2 Monotherapy (Dose Expansion): Duration of Response across all cohorts per RECIST v1.1 as assessed by Investigator and as assessed by independent review	Evaluation of anti-tumor activity of rezatapopt as a single agent	34 months for study (end of Phase 2)
Phase 2 Monotherapy (Dose Expansion): Disease Control Rate in ovarian cancer cohort per RECIST v1.1 as assessed by Investigator and as assessed by independent review	Evaluation of anti-tumor activity of rezatapopt as a single agent	34 months for study (end of Phase 2)
Phase 2 Monotherapy (Dose Expansion): Disease Control Rate across all cohorts per RECIST v1.1 as assessed by Investigator and as assessed by independent review	Evaluation of anti-tumor activity of rezatapopt as a single agent	34 months for study (end of Phase 2)
Phase 2 Monotherapy (Dose Expansion): Progression Free Survival in ovarian cancer cohort per RECIST v1.1 as assessed by Investigator and as assessed by independent review	Evaluation of anti-tumor activity of rezatapopt as a single agent	34 months for study (end of Phase 2)
Phase 2 Monotherapy (Dose Expansion): Progression Free Survival across all cohorts per RECIST v1.1 as assessed by Investigator and as assessed by independent review	Evaluation of anti-tumor activity of rezatapopt as a single agent	34 months for study (end of Phase 2)
Phase 2 Monotherapy (Dose Expansion): Overall Survival in ovarian cancer cohort	Evaluation of anti-tumor activity of rezatapopt as a single agent	34 months for study (end of Phase 2)
Phase 2 Monotherapy (Dose Expansion): Overall Survival across all cohorts	Evaluation of anti-tumor activity of rezatapopt as a single agent	34 months for study (end of Phase 2)
Phase 1 Monotherapy: Blood plasma assessment to describe the concentration of PC14586 and metabolites when rezatapopt is administered orally.	Blood plasma concentration	Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 1b Combination Therapy: Blood plasma assessment to describe the concentration of rezatapopt and metabolites when rezatapopt is administered orally in combination with pembrolizumab.	Blood plasma concentration	Approximately 12 months per patient (30 months for treatment arm)
Phase 2 Monotherapy: Blood plasma assessment to describe the concentration of rezatapopt and metabolites when rezatapopt is administered orally.	Blood plasma concentration	Approximately 12 months per patient (75 months for Phase 1 and Phase 2)

Collaborators and Investigators

• Sponsor: PMV Pharmaceuticals, Inc
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Study Director: Marc Fellous, MD, Sr. Vice President of Medical Affairs

Publications and helpful links

General Publications

• 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.
• 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 Oct;21(24):3159-3166. doi: 10.1080/14796694.2025.2557176. Epub 2025 Sep 11.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 29, 2020
• Primary Completion (Estimated): August 15, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: October 1, 2020
• First Submitted That Met QC Criteria: October 7, 2020
• First Posted (Actual): October 14, 2020

Study Record Updates

• Last Update Posted (Actual): March 12, 2026
• Last Update Submitted That Met QC Criteria: March 10, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Phase 1; PD-1; PD-L1; Keytruda; p53 mutation; p53; TP53; pembrolizumab; Phase 1b; NGS; anti-PD-1; Phase 2; Phase 1/2; Next Generation Sequencing; combination; mAb; IgG4; PC14586; Y220C; PMV; PMV Pharma; TP53 mutation; p53 mutant; p53 reactivator; Merck; MSD; precision; Rezatapopt
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Pathologic Processes; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Intestinal Diseases; Respiratory Tract Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Uterine Diseases; Genital Diseases, Female; Lung Diseases; Endocrine Gland Neoplasms; Biliary Tract Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Colonic Diseases; Neoplastic Processes; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Gonadal Disorders; Skin Diseases; Breast Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Uterine Neoplasms; Gallbladder Diseases; Biliary Tract Neoplasms; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Prostatic Neoplasms; Lung Neoplasms; Colorectal Neoplasms; Ovarian Neoplasms; Breast Neoplasms; Neoplasm Metastasis; Carcinoma, Non-Small-Cell Lung; Head and Neck Neoplasms; Small Cell Lung Carcinoma; Triple Negative Breast Neoplasms; Endometrial Neoplasms; Gallbladder Neoplasms; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; pembrolizumab
• Other Study ID Numbers: PMV-586-101; KEYNOTE-D79 (Registry Identifier: Merck, Sharp & Dohme, LLC); MK-3475-D79 (Registry Identifier: Merck, Sharp & Dohme, LLC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No