The Evaluation of PC14586 in Patients With Advanced Solid Tumors Harboring a TP53 Y220C Mutation (PYNNACLE)

Official title

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)

Overview

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.

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.

Interventions

• Drug rezatapopt
  First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.
• Drug pembrolizumab
  Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.

Primary outcome measures

• Phase 1 Monotherapy (Dose Escalation): Determine the number and type of adverse events to characterize the safety of rezatapopt [Time frame: 40 months]
• Phase 1 Monotherapy (Dose Escalation): Establish the Recommended Phase 2 Dose (RP2D) [Time frame: 30 months]
• Phase 1 Monotherapy (Dose Escalation): Establish the maximum tolerated dose (MTD) (Phase 1) [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 12 months for treatment arm]
• Phase 2 Monotherapy (Dose Expansion): Response rate assessment to evaluate the clinical activity / efficacy of rezatapopt [Time frame: 34 months]
• Phase 2 Monotherapy (Dose Expansion): Response rate assessment to evaluate the clinical activity / efficacy of rezatapopt in ovarian cancer patients [Time frame: 34 months]

Secondary outcome measures (12)

• Phase 1 Monotherapy: PK profile of rezatapopt - Peak concentration (Cmax) [Time frame: 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) [Time frame: 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) [Time frame: 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) [Time frame: 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) [Time frame: 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 metabolites when rezatapopt is administered orally. [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 41 months for study (end of Phase 1)]
• Phase 1 Monotherapy (Dose Escalation): Overall Survival [Time frame: 41 months for study (end of Phase 1)]

Eligibility criteria

Inclusion criteria

• At least 18 years of age or 12 to 17 years of age after Safety Review Committee approval.
• Locally advanced or metastatic solid malignancy with a TP53 Y220C mutation
• Eastern Cooperative Oncology Group (ECOG) status of 0 or 1
• Previously treated with one or more lines of anticancer therapy and progressive disease
• Adequate organ function
• Measurable disease per RECIST v1.1 (Phase 2)

Additional Criteria for Inclusion in Phase 1b (rezatapopt) + pembrolizumab combination)

• Anti-PD-1/PD-L1 naive or must have progressed on treatment
• Measurable disease

Exclusion criteria

• Anti-cancer therapy within 21 days (or 5 half-lives) of receiving the study drug
• Radiotherapy within 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 33 centers

• University of California Irvine Chao Family Comprehensive Cancer Center — Irvine
• University of San Diego Moores Cancer Center — La Jolla
• UCLA Jonsson Comprehensive Cancer Center — Los Angeles
• USC Norris Comprehensive Cancer Center — Los Angeles
• Rocky Mountain Cancer Center — Denver
• Yale Cancer Center — New Haven
• Medical Oncology Hematology Consultants — Newark
• University of Miami - Sylvester Comprehensive Cancer Center — Miami
• … and 25 more centers

France · 9 centers

• ICANS - Institut de cancérologie Strasbourg Europe — Strasbourg
• Institut Bergonie — Bordeaux
• Institut Claudius Regaud — Toulouse
• EDOG Institut de Cancerologie de l'Ouest — Saint-Herblain
• Centre Jean Perrin — Clermont-Ferrand
• Institut Gustave Roussy — Villejuif
• Centre Léon Bérard Centre Régional de Lutte Contre Le Cancer — Lyon
• CHU de Nîmes — Nîmes
• … and 1 more center

Italy · 9 centers

• Fondazione Policlinico Universitario Agostino Gemelli IRCCS — Rome
• Istituti Fisioterapici Ospitalieri - Istituto Nazionale Tumori Regina Elena — Rome
• ASST Grande Ospedale Metropolitano Niguarda — Milan
• Fondazione IRCCS Istituto Nazionale Dei Tumori — Milan
• Istituto Europeo Di Oncologia — Milan
• Istituto Clinico Humanitas — Rozzano
• Fondazione del Piemonte per l'Oncologia (IRCCS) — Candiolo
• Humanitas San Pio X — Milan
• … and 1 more center

Spain · 7 centers

• START MADRID_Hospital Universitario Fundacion Jimenez Diaz — Madrid
• START MADRID_Hospital Universitario HM Sanchinarro - CIOCC — Madrid
• Instituto de Investigacion Oncologica Vall d'Hebron (VHIO) - EPON — Barcelona
• NEXT Oncology-Hospital Quironsalud Barcelona — Barcelona
• Hospital Universitario 12 de Octubre — Madrid
• START Rioja — Rioja
• Hospital Clinico Universitario de Valencia — Valencia

Australia · 5 centers

• Chris O'Brien Lifehouse Hospital — Camperdown
• Mater Cancer Care Centre — South Brisbane
• Flinders Medical Center — Bedford Park
• Monash Medical Centre — Clayton
• Linear Clinical Research — Nedlands

Germany · 5 centers

• Nationale Centrum für Tumorerkrankungen (NCT) Heidelberg — Heidelberg
• Universitätsklinikum Augsburg — Augsburg
• Asklepios Klinik Altona — Hamburg
• Universitätsklinikum Frankfurt — Frankfurt am Main
• Universitätsklinikum Essen — Essen

South Korea · 5 centers

• Asan Medical Center — Seoul
• National Cancer Center — Seoul
• Samsung Medical Center — Seoul
• Seoul University Hospital — Seoul
• Severance Hospital Yonsei University — Seoul

Singapore · 2 centers

• National University Hospital — Kent Ridge
• National Cancer Center of Singapore — Singapore

United Kingdom · 2 centers

• Sarah Cannon Research Institute UK — London
• Freeman Hospital — Newcastle upon Tyne

Publications

• 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 41740031
• 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. PMID 40932470
• 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. PMID 40543428

Identifiers

NCT: NCT04585750 · PMV-586-101 · KEYNOTE-D79 · MK-3475-D79

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗