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)

This Phase 1/2 study will assess the safety, tolerability, and efficacy of multiple dose levels of PC14586 (INN: rezatapopt) alone (monotherapy) and in combination with pembrolizumab in participants with advanced solid tumors containing a TP53 Y220C mutation.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; Head and Neck Cancer; Colorectal Cancer; Ovarian Cancer; Lung Cancer; Prostate Cancer; Metastatic Cancer; Advanced Solid Tumor; Endometrial Cancer; Metastatic Solid Tumor; Other Cancer; Advanced Malignant Neoplasm; Locally Advanced
• Intervention / Treatment: Drug: PC14586; Drug: pembrolizumab

Detailed Description

PC14586 (INN: rezatapopt) is a first-in-class, oral, small molecule p53 reactivator that is selective for the TP53 Y220C mutation.

The primary objective of Phase 1 Monotherapy is to establish the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of PC14586 (INN: rezatapopt). Secondary objectives are to characterize the pharmacokinetic (PK) properties, safety and tolerability, and to assess preliminary efficacy including overall response rate (ORR).

The primary objective of Phase 1b Combination Therapy is to establish the MTD/RP2D of PC14586 (INN: 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 PC14586 (INN: rezatapopt) when administered in combination with pembrolizumab, including ORR.

The primary objective of Phase 2 Monotherapy is to evaluate the efficacy of PC14586 (INN: rezatapopt) at the RP2D including the 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, PK properties, quality of life, and other efficacy measures of PC14586 (INN: rezatapopt) at the RP2D.

• Study Type: Interventional
• Enrollment (Estimated): 230
• 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
      • Not yet recruiting
      • Chris O'Brien Lifehouse Hospital
      • Contact: Peter Grimison, MD
  • Victoria
    • Clayton, Victoria, Australia
      • Not yet recruiting
      • Monash Medical Centre
      • Contact: Amy Body, MD
  • Western Australia
    • Nedlands, Western Australia, Australia
      • Not yet recruiting
      • Linear Clinical Research
      • Contact: Michael Millward, MD
• France
  • Lyon, France
    • Not yet recruiting
    • Centre Léon Bérard Centre Régional de Lutte Contre Le Cancer
    • Contact: Isabelle Ray-Coquard, MD
  • Bas-Rhin
    • Strasbourg, Bas-Rhin, France
      • Not yet recruiting
      • ICANS - Institut de cancérologie Strasbourg Europe
      • Contact: Lauriane Eberst, MD
  • Gironde
    • Bordeaux, Gironde, France
      • Not yet recruiting
      • Institut Bergonié
      • Contact: Antoine Italiano, MD
  • Haute-Garonne
    • Toulouse, Haute-Garonne, France
      • Not yet recruiting
      • Institut Claudius Regaud
      • Contact: Carlos-Alberto Gomez-Roca, MD
  • Loire-Atlantique
    • Saint-Herblain, Loire-Atlantique, France
      • Not yet recruiting
      • EDOG Institut de Cancerologie de l'Ouest
      • Contact: Jean-Sebastien Frenel, MD
  • Puy-de-Dôme
    • Clermont-Ferrand, Puy-de-Dôme, France
      • Not yet recruiting
      • Centre Jean Perrin
      • Contact: Xavier Durando, MD
  • Val-de-Marne
    • Villejuif, Val-de-Marne, France
      • Not yet recruiting
      • Institut Gustave Roussy
      • Contact: Santiago Ponce Aix, MD
• Germany
  • Hamburg, Germany
    • Not yet recruiting
    • Asklepios Klinik Altona
    • Contact: Dirk Arnold, MD
  • Baden-Württemberg
    • Heidelberg, Baden-Württemberg, Germany
      • Not yet recruiting
      • Nationale Centrum für Tumorerkrankungen (NCT) Heidelberg
      • Contact: Martin Haag, MD
  • Bayern
    • Augsburg, Bayern, Germany
      • Not yet recruiting
      • Universitätsklinikum Augsburg
      • Contact: Rainer Claus, MD
  • Hessen
    • Frankfurt, Hessen, Germany
      • Not yet recruiting
      • Universitätsklinikum Frankfurt
      • Contact: Martin Sebastian, MD
  • Nordrhein-Westfalen
    • Essen, Nordrhein-Westfalen, Germany
      • Not yet recruiting
      • Universitätsklinikum Essen
      • Contact: Marcel Wiesweg, MD
• Italy
  • Lazio
    • Rome, Lazio, Italy
      • Not yet recruiting
      • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
      • Contact: Domenica Lorusso, MD
    • Rome, Lazio, Italy
      • Not yet recruiting
      • Istituti Fisioterapici Ospitalieri - Istituto Nazionale Tumori Regina Elena
      • Contact: Lorenza Landi, MD
  • Lombardia
    • Milano, Lombardia, Italy
      • Not yet recruiting
      • ASST Grande Ospedale Metropolitano Niguarda
      • Contact: Salvatore Siena, MD
    • Milano, Lombardia, Italy
      • Not yet recruiting
      • Fondazione IRCCS Istituto Nazionale dei Tumori
      • Contact: Massimo Di Nicola, MD
    • Milano, Lombardia, Italy
      • Not yet recruiting
      • Istituto Europeo di Oncologia
      • Contact: Giuseppe Curigliano, MD
    • Rozzano, Lombardia, Italy
      • Not yet recruiting
      • Istituto Clinico Humanitas
      • Contact: Armando Santoro, MD
  • Torino
    • Candiolo, Torino, Italy
      • Not yet recruiting
      • Fondazione del Piemonte per l'Oncologia (IRCCS)
      • Contact: Vanesa Gregorc, MD
• Korea, Republic of
  • Seoul, Korea, Republic of
    • Not yet recruiting
    • Asan Medical Center
    • Contact: Dae Ho Lee, MD
• Singapore
  • Kent Ridge, Singapore
    • Not yet recruiting
    • National University Hospital
    • Contact: David Shao Peng Tan, MD
• Spain
  • Barcelona, Spain
    • Not yet recruiting
    • Instituto de Investigacion Oncologica Vall d'Hebron (VHIO) - EPON
    • Contact: Irene Braña, MD
  • Barcelona, Spain
    • Not yet recruiting
    • NEXT Oncology-Hospital Quironsalud Barcelona
    • Contact: Elena Garralda, MD
  • Madrid, Spain
    • Not yet recruiting
    • START Madrid_Hospital Universitario Fundacion Jimenez Diaz
    • Contact: Victor Moreno Garcia, MD
  • Madrid, Spain
    • Not yet recruiting
    • START MADRID_Hospital Universitario HM Sanchinarro - CIOCC
    • Contact: Maria Jose De Miguel Luken, MD
  • Valencia, Spain
    • Not yet recruiting
    • Hospital Clínico Universitario de Valencia
    • Contact: Desamparados Roda Perez, MD
• United Kingdom
  • Middlesex
    • London, Middlesex, United Kingdom
      • Not yet recruiting
      • Sarah Cannon Research Institute UK
      • Contact: Elisa Fontana, MD, PhD
  • Tyne And Wear
    • Newcastle Upon Tyne, Tyne And Wear, United Kingdom
      • Not yet recruiting
      • Royal Victoria Infirmary
      • Contact: Alastair Greystoke, MB ChB PhD
• United States
  • California
    • Duarte, California, United States, 91010
      • Not yet recruiting
      • City of Hope
      • Contact: Stephen Gruber, MD
    • La Jolla, California, United States, 92093
      • Not yet recruiting
      • University of California, San Diego
      • Contact: Shumei Kato, MD
    • Los Angeles, California, United States, 90033
      • Recruiting
      • USC Norris Comprehensive Cancer Center
      • Contact: Anthony El-Khoueiry, MD
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Recruiting
      • Yale Cancer Center
      • Contact: Patricia LoRusso, MD
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami - Sylvester Comprehensive Cancer Center
      • Contact: Gilberto de Lima Lopes Jr., MD
    • West Palm Beach, Florida, United States, 33401
      • Not yet recruiting
      • Florida Cancer Specialists South
      • Contact: Ivor Percent, MD
  • Indiana
    • Indianapolis, Indiana, United States, 46240
      • Recruiting
      • Indiana University
      • Contact: Mateusz Opyrchal, 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
    • Buffalo, New York, United States, 14203
      • Not yet recruiting
      • Roswell Park Comprehensive Cancer Institute
      • Contact: Bailey Fitzgerald, MD
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial sloan kettering
      • Contact: Alison Schram, MD
  • 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: Thomas Karasic, MD
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Not yet recruiting
      • Medical University of South Carolina
      • Contact: John Kaczmar, MD
  • 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
    • Houston, Texas, United States, 77030
      • Recruiting
      • The University of Texas MD Anderson Cancer Center
      • Contact: Escaterina 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: John Thompson, MD
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • Not yet 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.
• Advanced 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 (PC14586 (INN: 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 inhibitors or inducers, medications with a known risk of QT/QTc prolongation, or proton pump inhibitors
• 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 (PC14586 monotherapy)

• Known KRAS mutation, defined as a single nucleotide variant (SNV) (Phase 2)

Additional Criteria for Exclusion from Phase 1b (PC14586 (INN: 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 PC14586 (INN: 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 1 Monotherapy Dose Escalation; Multiple dose levels of daily oral PC14586 (INN: 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 PC14586 (INN: rezatapopt) to recommend a Phase 2 dose (RP2D).	Drug: PC14586; First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.; Other Names: rezatapopt
Experimental: Phase 1b Combination Therapy Dose Escalation, Part 1; Multiple dose levels of daily oral PC14586 (INN: 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 PC14586 (INN: rezatapopt) when administered in combination with pembrolizumab.	Drug: PC14586; First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.; Other Names: rezatapopt; Drug: pembrolizumab; Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.; Other Names: MK-3475; KEYTRUDA®; KEYNOTE-D79; MK-3475-D79
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: PC14586; First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.; Other Names: rezatapopt; Drug: pembrolizumab; Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.; Other Names: MK-3475; KEYTRUDA®; KEYNOTE-D79; MK-3475-D79
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 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 relapsed/refractory patients.	Drug: PC14586; First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.; Other Names: rezatapopt; Drug: pembrolizumab; Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.; Other Names: MK-3475; KEYTRUDA®; KEYNOTE-D79; MK-3475-D79
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: PC14586; First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.; Other Names: rezatapopt
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: PC14586; First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.; Other Names: rezatapopt
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: PC14586; First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.; Other Names: rezatapopt
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: PC14586; First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.; Other Names: rezatapopt
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: PC14586; First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.; Other Names: rezatapopt

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1 Monotherapy (Dose Escalation): Determine the number and type of adverse events to characterize the safety of PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: rezatapopt) when administered in combination with pembrolizumab	Incidence of dose limiting toxicities (DLTs) during the first 28 days of treatment with PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: rezatapopt)	Overall response rate in accordance with Response Evaluation Criteria across all cohorts (RECIST) v.1.1 as assessed by independent review	34 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Peak concentration (Cmax)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)	Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Time of peak concentration (Tmax)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)	Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 1 Monotherapy: PK profile of PC14586 (INN: 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 PC14586 (INN: rezatapopt)	Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 1 Monotherapy: PK profile of PC14586 (INN: 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 PC14586 (INN: rezatapopt)	Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Trough observed concentrations (Ctrough/Ctau)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)	Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 1 Monotherapy: Blood plasma assessment to describe the concentration of PC14586 and metabolite (M1) when PC14586 (INN: rezatapopt) is administered orally.	Blood plasma concentration	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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: rezatapopt) as a single agent	41 months for study (end of Phase 1)
Phase 1b Combination Therapy: PK profile of PC14586 (INN: rezatapopt) in combination with pembrolizumab - Peak concentration (Cmax)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)	Approximately 12 months per patient (30 months for treatment arm)
Phase 1b Combination Therapy: PK profile of PC14586 (INN: rezatapopt) in combination with pembrolizumab - Time of peak concentration (Tmax)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)	Approximately 12 months per patient (30 months for treatment arm)
Phase 1b Combination Therapy: PK profile of PC14586 (INN: 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 PC14586 (INN: rezatapopt)	Approximately 12 months per patient (30 months for treatment arm)
Phase 1b Combination Therapy: PK profile of PC14586 (INN: 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 PC14586 (INN: rezatapopt)	Approximately 12 months per patient (30 months for treatment arm)
Phase 1b Combination Therapy: PK profile of PC14586 (INN: rezatapopt) in combination with pembrolizumab - Trough observed concentrations (Ctrough/Ctau)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)	Approximately 12 months per patient (30 months for treatment arm)
Phase 1b Combination Therapy: Blood plasma assessment to describe the concentration of PC14586 (INN: rezatapopt) and metabolite (M1) when PC14586 (INN: rezatapopt) is administered orally in combination with pembrolizumab.	Blood plasma concentration	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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: rezatapopt) in combination with pembrolizumab	30 months for study (end of Phase 1b)
Phase 2 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Time of peak concentration (Tmax)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)	Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 2 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Peak concentration (Cmax)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)	Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 2 Monotherapy: PK profile of PC14586 (INN: 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 PC14586 (INN: rezatapopt)	Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 2 Monotherapy: PK profile of PC14586 (INN: 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 PC14586 (INN: rezatapopt)	Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 2 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Trough observed concentrations (Ctrough/Ctau)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)	Approximately 12 months per patient (75 months for Phase 1 and Phase 2)
Phase 2 Monotherapy: Blood plasma assessment to describe the concentration of PC14586 (INN: rezatapopt) and metabolite (M1) when PC14586 (INN: rezatapopt) is administered orally.	Blood plasma concentration	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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: 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 PC14586 (INN: rezatapopt) as a single agent	34 months for study (end of Phase 2)
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)

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): October 29, 2020
• Primary Completion (Estimated): March 17, 2026
• Study Completion (Estimated): July 14, 2026

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 (Estimated): February 9, 2024
• Last Update Submitted That Met QC Criteria: February 7, 2024
• Last Verified: February 1, 2024

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 Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Neoplasms; Endometrial Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; 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