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RecruitingInterventionalPhase 1/Phase 2

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)

NCT ID: NCT04585750Sponsor: PMV Pharmaceuticals, IncLast updated: 2026-03-12

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.

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.

Arms & interventions

  • Drugrezatapopt

    First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.

  • Drugpembrolizumab

    Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.

Outcome measures

Primary

  • 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

    Time frame: 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

    Time frame: 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

    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

    Number of participants with treatment related adverse events

    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

    Incidence of dose limiting toxicities (DLTs) during the first 28 days of treatment with rezatapopt

    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

    RP2D will be determined using available safety and pharmacokinetics and pharmacodynamics data

    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

    Number of participants with treatment related adverse events

    Time frame: 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

    Time frame: 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

    Time frame: 34 months

Secondary

  • 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)

  • Phase 1b Combination Therapy: PK profile of rezatapopt in combination with pembrolizumab - Peak concentration (Cmax)

    Time frame: 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)

    Time frame: 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)

    Time frame: 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)

    Time frame: 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)

    Time frame: Approximately 12 months per patient (30 months for treatment arm)

  • Phase 1b Combination Therapy: Blood plasma assessment to describe the concentration of rezatapopt and metabolites when rezatapopt is administered orally in combination with pembrolizumab.

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 30 months for study (end of Phase 1b)

  • Phase 1b Combination Therapy: Overall Survival

    Time frame: 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

    Time frame: 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

    Time frame: 30 months for study (end of Phase 1b)

  • Phase 2 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 2 Monotherapy: PK profile of rezatapopt - Peak concentration (Cmax)

    Time frame: 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)

    Time frame: 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)

    Time frame: 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)

    Time frame: Approximately 12 months per patient (75 months for Phase 1 and Phase 2)

  • Phase 2 Monotherapy: Blood plasma assessment to describe the concentration of rezatapopt and metabolites when rezatapopt is administered orally.

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 34 months for study (end of Phase 2)

  • Phase 2 Monotherapy (Dose Expansion): Overall Survival in ovarian cancer cohort

    Time frame: 34 months for study (end of Phase 2)

  • Phase 2 Monotherapy (Dose Expansion): Overall Survival across all cohorts

    Time frame: 34 months for study (end of Phase 2)

  • Phase 2 Monotherapy (Dose Expansion): Quality of life assessment

    Time frame: Evaluated at every visit. 34 months for treatment arm (end of Phase 2)

Eligibility criteria

Sex: AllAge: 12 Years and olderHealthy volunteers: No
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 locations (32)

University of California Irvine Chao Family Comprehensive Cancer Center

Irvine, California, 92868

Recruiting
Zhaohui Arter, MD · Contact

University of San Diego Moores Cancer Center

La Jolla, California, 92093

Not Yet Recruiting
Shumei Kato, MD · Contact

UCLA Jonsson Comprehensive Cancer Center

Los Angeles, California, 90024

Recruiting
Gottfried Konecny, MD · Contact

USC Norris Comprehensive Cancer Center

Los Angeles, California, 90033

Recruiting
Anthony El-Khoueiry, MD · Contact

Rocky Mountain Cancer Center

Denver, Colorado, 80218

Recruiting
Allen Cohn, MD · Contact

Yale Cancer Center

New Haven, Connecticut, 06519

Recruiting
Patricia LoRusso, MD · Contact

Medical Oncology Hematology Consultants

Newark, Delaware, 19713

Recruiting
Jamal Misleh, MD · Contact

University of Miami - Sylvester Comprehensive Cancer Center

Miami, Florida, 33136

Recruiting
Gilberto de Lima Lopes Jr., MD · Contact

Advent Health

Orlando, Florida, 32803

Not Yet Recruiting
Robert Holloway, MD · Contact

Florida Cancer Specialists South

Port Charlotte, Florida, 33980

Recruiting
Ivor Percent, MD · Contact

Massachusetts General Hospital

Boston, Massachusetts, 02114

Recruiting
Aparna Parikh, MD · Contact

Dana Farber Cancer Institute

Boston, Massachusetts, 02215

Recruiting
Geoffrey Shapiro, MD, PhD · Contact

Karmanos Cancer Institute

Detroit, Michigan, 48201

Recruiting
Dipesh Uprety, MD · Contact

Columbia University

New York, New York, 10032

Not Yet Recruiting
June Hou, MD · Contact

Memorial Sloan Kettering

New York, New York, 10065

Recruiting
Alison Schram, MD · Contact

Duke University

Durham, North Carolina, 27705

Recruiting
Niharika Mettu, MD, PhD · Contact

The Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio, 44195

Recruiting
Dale Shepard, MD · Contact

University of Oklahoma

Oklahoma City, Oklahoma, 73104

Recruiting
Debra Richardson, MD · Contact

Oregon Health & Science University (OHSU)

Portland, Oregon, 97210

Recruiting
Shivaani Kummar, MD · Contact

Abramson Cancer Center of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104

Recruiting
Lainie Martin, MD · Contact

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213

Not Yet Recruiting
Sarah Taylor, MD, PhD · Contact

WellSpan York Cancer Center

York, Pennsylvania, 17403

Recruiting
Ikechukwu Akunyili, MD · Contact

Medical University of South Carolina

Charleston, South Carolina, 29425

Terminated

Sarah Cannon Research Institute

Nashville, Tennessee, 37203

Recruiting
Melissa Johnson, MD · Contact

New Experimental Therapeutics - NEXT Oncology

Austin, Texas, 78705

Recruiting
Anthony Tolcher, MD · Contact

UTSW - Moody Outpatient Center - Parkland Health

Dallas, Texas, 75235

Not Yet Recruiting
David Miller, MD · Contact

UT Southwest Simmons Cancer Center

Dallas, Texas, 75390

Recruiting
David Miller, MD · Contact

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030

Recruiting
Ecaterina Dumbrava, MD · Contact

New Experimental Therapeutics of San Antonio - NEXT Oncology

San Antonio, Texas, 78229

Recruiting
Anthony Tolcher, MD · Contact

Virginia Cancer Specialists

Fairfax, Virginia, 22031

Recruiting
Alexander Spira, MD · Contact

University of Washington, Fred Hutchinson Cancer Center

Seattle, Washington, 98109

Recruiting
Andrew Coveler, MD · Contact

University of Wisconsin Carbone Cancer Center

Madison, Wisconsin, 53705

Recruiting
Nataliya Uboha, MD, PhD · Contact

References

  • 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.(PubMed)
  • 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.(PubMed)
  • 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.(PubMed)