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

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ClinicalTrials.gov Identifier: NCT04585750
Recruitment Status : Recruiting
First Posted : October 14, 2020
Last Update Posted : May 8, 2024
Sponsor:
Collaborator:
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
PMV Pharmaceuticals, Inc

Tracking Information
First Submitted Date  ICMJE October 1, 2020
First Posted Date  ICMJE October 14, 2020
Last Update Posted Date May 8, 2024
Actual Study Start Date  ICMJE October 29, 2020
Estimated Primary Completion Date March 17, 2026   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 7, 2024)
  • Phase 1 Monotherapy (Dose Escalation): Determine the number and type of adverse events to characterize the safety of PC14586 (INN: rezatapopt) [ Time Frame: 40 months ]
    Number of participants with treatment related adverse events
  • Phase 1 Monotherapy (Dose Escalation): Establish the Recommended Phase 2 Dose (RP2D) [ Time Frame: 30 months ]
    RP2D will be determined using available safety and pharmacokinetics and pharmacodynamics data
  • 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 ]
    Incidence of dose limiting toxicities (DLTs) during the first 28 days of treatment with PC14586 (INN: rezatapopt)
  • 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 [ Time Frame: 18 months for treatment arm ]
    Number of participants with treatment related adverse events
  • Phase 1b Combination Therapy (Part 1: Dose Escalation): Establish the maximum tolerated dose (MTD) of PC14586 (INN: rezatapopt) when administered in combination with pembrolizumab [ Time Frame: The first 28 days of combination treatment arm (starting on Day -7) per patient ]
    Incidence of dose limiting toxicities (DLTs) during the first 28 days of treatment with PC14586 (INN: rezatapopt)
  • 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 [ Time Frame: 18 months ]
    RP2D will be determined using available safety and pharmacokinetics and pharmacodynamics data
  • 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 [ Time Frame: 12 months for treatment arm ]
    Number of participants with treatment related adverse events
  • Phase 2 Monotherapy (Dose Expansion): Response rate assessment to evaluate the clinical activity / efficacy of PC14586 (INN: rezatapopt) [ Time Frame: 34 months ]
    Overall response rate in accordance with Response Evaluation Criteria across all cohorts (RECIST) v.1.1 as assessed by independent review
Original Primary Outcome Measures  ICMJE
 (submitted: October 7, 2020)
  • Characterize the safety of PC14586 [ Time Frame: 48 months for study (Phase 1 and 2) ]
    Number of participants with treatment related adverse events
  • Establish the maximum tolerated dose (MTD) (Phase 1) [ Time Frame: The first 21 days of treatment (Cycle 1) per patient ]
    Incidence of dose limiting toxicities (DLTs) during the first 21-day cycle of PC14586
  • Evaluate clinical activity / efficacy of PC14586 (Phase 2) [ Time Frame: 48 months for study (Phase 1 and 2) ]
    Overall response rate in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 as assessed by Independent Review Committee
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 7, 2024)
  • Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Peak concentration (Cmax) [ Time Frame: Approximately 12 months per patient (75 months for Phase 1 and Phase 2) ]
    Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)
  • Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Time of peak concentration (Tmax) [ Time Frame: Approximately 12 months per patient (75 months for Phase 1 and Phase 2) ]
    Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)
  • 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) [ Time Frame: Approximately 12 months per patient (75 months for Phase 1 and Phase 2) ]
    Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)
  • Phase 1 Monotherapy: PK profile of PC14586 (INN: 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) ]
    Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)
  • Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Trough observed concentrations (Ctrough/Ctau) [ Time Frame: Approximately 12 months per patient (75 months for Phase 1 and Phase 2) ]
    Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)
  • Phase 1 Monotherapy: Blood plasma assessment to describe the concentration of PC14586 and metabolite (M1) when PC14586 (INN: rezatapopt) is administered orally. [ Time Frame: Approximately 12 months per patient (75 months for Phase 1 and Phase 2) ]
    Blood plasma concentration
  • 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) ]
    Evaluation of preliminary anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
  • 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) ]
    Evaluation of preliminary anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
  • 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) ]
    Evaluation of preliminary anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
  • 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) ]
    Evaluation of preliminary anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
  • 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) ]
    Evaluation of preliminary anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
  • Phase 1 Monotherapy (Dose Escalation): Overall Survival [ Time Frame: 41 months for study (end of Phase 1) ]
    Evaluation of preliminary anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
  • Phase 1b Combination Therapy: PK profile of PC14586 (INN: rezatapopt) in combination with pembrolizumab - Peak concentration (Cmax) [ Time Frame: Approximately 12 months per patient (30 months for treatment arm) ]
    Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)
  • Phase 1b Combination Therapy: PK profile of PC14586 (INN: rezatapopt) in combination with pembrolizumab - Time of peak concentration (Tmax) [ Time Frame: Approximately 12 months per patient (30 months for treatment arm) ]
    Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)
  • 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) [ Time Frame: Approximately 12 months per patient (30 months for treatment arm) ]
    Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)
  • 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) [ Time Frame: Approximately 12 months per patient (30 months for treatment arm) ]
    Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)
  • Phase 1b Combination Therapy: PK profile of PC14586 (INN: rezatapopt) in combination with pembrolizumab - Trough observed concentrations (Ctrough/Ctau) [ Time Frame: Approximately 12 months per patient (30 months for treatment arm) ]
    Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)
  • 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. [ Time Frame: Approximately 12 months per patient (30 months for treatment arm) ]
    Blood plasma concentration
  • 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) ]
    Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) in combination with pembrolizumab
  • 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) ]
    Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) in combination with pembrolizumab
  • 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) ]
    Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) in combination with pembrolizumab
  • 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) ]
    Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) in combination with pembrolizumab
  • Phase 1b Combination Therapy: Overall Survival [ Time Frame: 30 months for study (end of Phase 1b) ]
    Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) in combination with pembrolizumab
  • Phase 1b Combination Therapy: Determine the number and type of adverse events to characterize the safety of PC14586 (INN: rezatapopt) [ Time Frame: 30 months for study (end of Phase 1b) ]
    Number of participants with treatment related adverse events
  • 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) ]
    Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) in combination with pembrolizumab
  • Phase 2 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Time of peak concentration (Tmax) [ Time Frame: Approximately 12 months per patient (75 months for Phase 1 and Phase 2) ]
    Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)
  • Phase 2 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Peak concentration (Cmax) [ Time Frame: Approximately 12 months per patient (75 months for Phase 1 and Phase 2) ]
    Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)
  • 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) [ Time Frame: Approximately 12 months per patient (75 months for Phase 1 and Phase 2) ]
    Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)
  • Phase 2 Monotherapy: PK profile of PC14586 (INN: 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) ]
    Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)
  • Phase 2 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Trough observed concentrations (Ctrough/Ctau) [ Time Frame: Approximately 12 months per patient (75 months for Phase 1 and Phase 2) ]
    Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of PC14586 (INN: rezatapopt)
  • Phase 2 Monotherapy: Blood plasma assessment to describe the concentration of PC14586 (INN: rezatapopt) and metabolite (M1) when PC14586 (INN: rezatapopt) is administered orally. [ Time Frame: Approximately 12 months per patient (75 months for Phase 1 and Phase 2) ]
    Blood plasma concentration
  • Phase 2 Monotherapy (Dose Expansion): Determine the number and type of adverse events to characterize the safety of PC14586 (INN: rezatapopt) [ Time Frame: 34 months for study (end of Phase 2) ]
    Number of participants with treatment related adverse events
  • 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) ]
    Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
  • 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) ]
    Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
  • 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) ]
    Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
  • 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) ]
    Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
  • 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) ]
    Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
  • 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) ]
    Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
  • 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) ]
    Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
  • 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) ]
    Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
  • 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) ]
    Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
  • 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) ]
    Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
  • Phase 2 Monotherapy (Dose Expansion): Overall Survival in ovarian cancer cohort [ Time Frame: 34 months for study (end of Phase 2) ]
    Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
  • Phase 2 Monotherapy (Dose Expansion): Overall Survival across all cohorts [ Time Frame: 34 months for study (end of Phase 2) ]
    Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
  • Phase 2 Monotherapy (Dose Expansion): Quality of life assessment [ Time Frame: Evaluated at every visit. 34 months for treatment arm (end of Phase 2) ]
    Changes from baseline in quality of life as measured by a validated instrument, for participants 18 and older
Original Secondary Outcome Measures  ICMJE
 (submitted: October 7, 2020)
  • Characterise the pharmacokinetics (PK) of PC14586 and metabolites (Phase 1 and 2) [ Time Frame: Approximately 12 months per patient (48 months for study) ]
    Blood plasma concentration
  • Assess clinical activity / efficacy of PC14586 (Phase 1) [ Time Frame: 20 months for study (end of Phase 1) ]
    Overall response rate in accordance with Response Evaluation Criteria in Solid Tumors
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Evaluation of PC14586 in Patients With Advanced Solid Tumors Harboring a TP53 Y220C Mutation (PYNNACLE)
Official Title  ICMJE 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)
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

During Phase 1 Monotherapy (Dose Escalation), participants will be assigned a dose level using an accelerated titration design in the initial dose cohorts, followed by a modified toxicity probability interval (mTPI) design in subsequent dose cohorts.

During Part 1 of the Ph 1b Combination Therapy, patients will be assigned a dose level using mTPI design. A recommended PC14586 (INN: rezatapopt) Phase 2 Dose (RP2D) when administered in combination with pembrolizumab will be selected at the end of Phase 1b Part 1, and the RP2D will be assigned to all participants in Part 2.

During Phase 2 Monotherapy the Recommended Phase 2 Dose (RP2D) selected at the end of Phase 1 Monotherapy and in Phase 2 (Dose Expansion) the RP2D will be assigned to all participants. Participants will be assigned to one of five cohorts: ovarian cancer, lung cancer, breast cancer, endometrial cancer, or other solid tumors.

Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Advanced Solid Tumor
  • Advanced Malignant Neoplasm
  • Metastatic Cancer
  • Metastatic Solid Tumor
  • Lung Cancer
  • Ovarian Cancer
  • Endometrial Cancer
  • Prostate Cancer
  • Colorectal Cancer
  • Breast Cancer
  • Other Cancer
  • Locally Advanced
  • Head and Neck Cancer
Intervention  ICMJE
  • Drug: PC14586
    First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.
    Other Name: rezatapopt
  • Drug: pembrolizumab
    Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.
    Other Names:
    • KEYTRUDA®
    • MK-3475
    • KEYNOTE-D79
    • MK-3475-D79
Study Arms  ICMJE
  • 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).
    Intervention: Drug: PC14586
  • 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.
    Interventions:
    • Drug: PC14586
    • Drug: pembrolizumab
  • 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.
    Interventions:
    • Drug: PC14586
    • Drug: pembrolizumab
  • 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.
    Interventions:
    • Drug: PC14586
    • Drug: pembrolizumab
  • 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.
    Intervention: Drug: 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.
    Intervention: Drug: 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.
    Intervention: Drug: 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.
    Intervention: Drug: 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.
    Intervention: Drug: PC14586
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 7, 2024)		 230
Original Estimated Enrollment  ICMJE
 (submitted: October 7, 2020)		 130
Estimated Study Completion Date  ICMJE July 14, 2026
Estimated Primary Completion Date March 17, 2026   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: PMV Pharma Clinical Study Information Center (609) 235-4038 clinicaltrials@pmvpharma.com
Listed Location Countries  ICMJE Australia,   France,   Germany,   Italy,   Korea, Republic of,   Singapore,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04585750
Other Study ID Numbers  ICMJE PMV-586-101
KEYNOTE-D79 ( Registry Identifier: Merck, Sharp & Dohme, LLC )
MK-3475-D79 ( Registry Identifier: Merck, Sharp & Dohme, LLC )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party PMV Pharmaceuticals, Inc
Original Responsible Party Same as current
Current Study Sponsor  ICMJE PMV Pharmaceuticals, Inc
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Merck Sharp & Dohme LLC
Investigators  ICMJE
Study Director: Marc Fellous, MD Vice President of Medical Affairs
PRS Account PMV Pharmaceuticals, Inc
Verification Date May 2024

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP