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

• ClinicalTrials.gov Identifier: NCT04585750
• Recruitment Status: Recruiting
• First Posted: October 14, 2020
• Last Update Posted: February 9, 2024
• Sponsor: PMV Pharmaceuticals, Inc
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): PMV Pharmaceuticals, Inc

Study Description

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.

Condition or disease	Intervention/treatment	Phase
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	Drug: PC14586; Drug: pembrolizumab	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 230 participants
• 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
• 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)
• Actual Study Start Date: October 29, 2020
• Estimated Primary Completion Date: March 17, 2026
• Estimated Study Completion Date: July 14, 2026

Arms and Interventions

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 Name: 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 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
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 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
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 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
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 Name: 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 Name: 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 Name: 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 Name: 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 Name: rezatapopt

Outcome Measures

Primary Outcome Measures :

1. 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
2. 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
3. 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)
4. 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
5. 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)
6. 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
7. 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
8. 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

Secondary Outcome Measures :

1. 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)
2. 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)
3. 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)
4. 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)
5. 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)
6. 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
7. 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
8. 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
9. 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
10. 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
11. 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
12. 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
13. 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)
14. 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)
15. 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)
16. 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)
17. 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)
18. 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
19. 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
20. 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
21. 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
22. 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
23. 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
24. 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
25. 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
26. 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)
27. 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)
28. 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)
29. 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)
30. 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)
31. 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
32. 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
33. 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
34. 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
35. 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
36. 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
37. 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
38. 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
39. 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
40. 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
41. 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
42. 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
43. 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
44. 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
45. 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

Eligibility Criteria

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

Criteria

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)

Contacts and Locations

Contacts

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

Locations

United States, California

City of Hope; Not yet recruiting

Duarte, California, United States, 91010

Contact: Stephen Gruber, MD

University of California, San Diego; Not yet recruiting

La Jolla, California, United States, 92093

Contact: Shumei Kato, MD

USC Norris Comprehensive Cancer Center; Recruiting

Los Angeles, California, United States, 90033

Contact: Anthony El-Khoueiry, MD

United States, Connecticut

Yale Cancer Center; Recruiting

New Haven, Connecticut, United States, 06519

Contact: Patricia LoRusso, MD

United States, Florida

University of Miami - Sylvester Comprehensive Cancer Center; Recruiting

Miami, Florida, United States, 33136

Contact: Gilberto de Lima Lopes Jr., MD

Florida Cancer Specialists South; Not yet recruiting

West Palm Beach, Florida, United States, 33401

Contact: Ivor Percent, MD

United States, Indiana

Indiana University; Recruiting

Indianapolis, Indiana, United States, 46240

Contact: Mateusz Opyrchal, MD

United States, Massachusetts

Massachusetts General Hospital; Recruiting

Boston, Massachusetts, United States, 02114

Contact: Aparna Parikh, MD

Dana Farber Cancer Institute; Recruiting

Boston, Massachusetts, United States, 02215

Contact: Geoffrey Shapiro, MD, PhD

United States, Michigan

Karmanos Cancer Institute; Recruiting

Detroit, Michigan, United States, 48201

Contact: Dipesh Uprety, MD

United States, New York

Roswell Park Comprehensive Cancer Institute; Not yet recruiting

Buffalo, New York, United States, 14203

Contact: Bailey Fitzgerald, MD

Memorial Sloan Kettering; Recruiting

New York, New York, United States, 10065

Contact: Alison Schram, MD

United States, Ohio

The Cleveland Clinic Taussig Cancer Center; Recruiting

Cleveland, Ohio, United States, 44195

Contact: Dale Shepard, MD

United States, Oklahoma

University of Oklahoma; Recruiting

Oklahoma City, Oklahoma, United States, 73104

Contact: Debra Richardson, MD

United States, Oregon

Oregon Health & Science University (OHSU); Recruiting

Portland, Oregon, United States, 97210

Contact: Shivaani Kummar, MD

United States, Pennsylvania

Abramson Cancer Center of the University of Pennsylvania; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Thomas Karasic, MD

United States, South Carolina

Medical University of South Carolina; Not yet recruiting

Charleston, South Carolina, United States, 29425

Contact: John Kaczmar, MD

United States, Tennessee

Sarah Cannon Research Institute; Recruiting

Nashville, Tennessee, United States, 37203

Contact: Melissa Johnson, MD

United States, Texas

New Experimental Therapeutics - NEXT Oncology; Recruiting

Austin, Texas, United States, 78705

Contact: Anthony Tolcher, MD

The University of Texas MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Contact: Escaterina Dumbrava, MD

New Experimental Therapeutics of San Antonio - NEXT Oncology; Recruiting

San Antonio, Texas, United States, 78229

Contact: Anthony Tolcher, MD

United States, Virginia

Virginia Cancer Specialists; Recruiting

Fairfax, Virginia, United States, 22031

Contact: Alexander Spira, MD

United States, Washington

University of Washington, Fred Hutchinson Cancer Center; Recruiting

Seattle, Washington, United States, 98109

Contact: John Thompson, MD

United States, Wisconsin

University of Wisconsin Carbone Cancer Center; Not yet recruiting

Madison, Wisconsin, United States, 53705

Contact: Nataliya Uboha, MD, PhD

Australia, New South Wales

Chris O'Brien Lifehouse Hospital; Not yet recruiting

Camperdown, New South Wales, Australia

Contact: Peter Grimison, MD

Australia, Victoria

Monash Medical Centre; Not yet recruiting

Clayton, Victoria, Australia

Contact: Amy Body, MD

Australia, Western Australia

Linear Clinical Research; Not yet recruiting

Nedlands, Western Australia, Australia

Contact: Michael Millward, MD

France

ICANS - Institut de cancérologie Strasbourg Europe; Not yet recruiting

Strasbourg, Bas-Rhin, France

Contact: Lauriane Eberst, MD

Institut Bergonie; Not yet recruiting

Bordeaux, Gironde, France

Contact: Antoine Italiano, MD

Institut Claudius Regaud; Not yet recruiting

Toulouse, Haute-Garonne, France

Contact: Carlos-Alberto Gomez-Roca, MD

EDOG Institut de Cancerologie de l'Ouest; Not yet recruiting

Saint-Herblain, Loire-Atlantique, France

Contact: Jean-Sebastien Frenel, MD

Centre Jean Perrin; Not yet recruiting

Clermont-Ferrand, Puy-de-Dôme, France

Contact: Xavier Durando, MD

Institut Gustave Roussy; Not yet recruiting

Villejuif, Val-de-Marne, France

Contact: Santiago Ponce Aix, MD

Centre Léon Bérard Centre Régional de Lutte Contre Le Cancer; Not yet recruiting

Lyon, France

Contact: Isabelle Ray-Coquard, MD

Germany

Nationale Centrum für Tumorerkrankungen (NCT) Heidelberg; Not yet recruiting

Heidelberg, Baden-Württemberg, Germany

Contact: Martin Haag, MD

Universitätsklinikum Augsburg; Not yet recruiting

Augsburg, Bayern, Germany

Contact: Rainer Claus, MD

Universitätsklinikum Frankfurt; Not yet recruiting

Frankfurt, Hessen, Germany

Contact: Martin Sebastian, MD

Universitätsklinikum Essen; Not yet recruiting

Essen, Nordrhein-Westfalen, Germany

Contact: Marcel Wiesweg, MD

Asklepios Klinik Altona; Not yet recruiting

Hamburg, Germany

Contact: Dirk Arnold, MD

Italy

Fondazione Policlinico Universitario Agostino Gemelli IRCCS; Not yet recruiting

Rome, Lazio, Italy

Contact: Domenica Lorusso, MD

Istituti Fisioterapici Ospitalieri - Istituto Nazionale Tumori Regina Elena; Not yet recruiting

Rome, Lazio, Italy

Contact: Lorenza Landi, MD

ASST Grande Ospedale Metropolitano Niguarda; Not yet recruiting

Milano, Lombardia, Italy

Contact: Salvatore Siena, MD

Fondazione IRCCS Istituto Nazionale Dei Tumori; Not yet recruiting

Milano, Lombardia, Italy

Contact: Massimo Di Nicola, MD

Istituto Europeo Di Oncologia; Not yet recruiting

Milano, Lombardia, Italy

Contact: Giuseppe Curigliano, MD

Istituto Clinico Humanitas; Not yet recruiting

Rozzano, Lombardia, Italy

Contact: Armando Santoro, MD

Fondazione del Piemonte per l'Oncologia (IRCCS); Not yet recruiting

Candiolo, Torino, Italy

Contact: Vanesa Gregorc, MD

Korea, Republic of

Asan Medical Center; Not yet recruiting

Seoul, Korea, Republic of

Contact: Dae Ho Lee, MD

Singapore

National University Hospital; Not yet recruiting

Kent Ridge, Singapore

Contact: David Shao Peng Tan, MD

Spain

Instituto de Investigacion Oncologica Vall d'Hebron (VHIO) - EPON; Not yet recruiting

Barcelona, Spain

Contact: Irene Braña, MD

NEXT Oncology-Hospital Quironsalud Barcelona; Not yet recruiting

Barcelona, Spain

Contact: Elena Garralda, MD

START MADRID_Hospital Universitario Fundacion Jimenez Diaz; Not yet recruiting

Madrid, Spain

Contact: Victor Moreno Garcia, MD

START MADRID_Hospital Universitario HM Sanchinarro - CIOCC; Not yet recruiting

Madrid, Spain

Contact: Maria Jose De Miguel Luken, MD

Hospital Clinico Universitario de Valencia; Not yet recruiting

Valencia, Spain

Contact: Desamparados Roda Perez, MD

United Kingdom

Sarah Cannon Research Institute UK; Not yet recruiting

London, Middlesex, United Kingdom

Contact: Elisa Fontana, MD, PhD

Royal Victoria Infirmary; Not yet recruiting

Newcastle Upon Tyne, Tyne And Wear, United Kingdom

Contact: Alastair Greystoke, MB ChB PhD

Sponsors and Collaborators

PMV Pharmaceuticals, Inc

Merck Sharp & Dohme LLC

Investigators

• Study Director: Marc Fellous, MD; Vice President of Medical Affairs

More Information

• Responsible Party: PMV Pharmaceuticals, Inc
• ClinicalTrials.gov Identifier: NCT04585750
• Other Study ID Numbers: PMV-586-101; KEYNOTE-D79 ( Registry Identifier: Merck, Sharp & Dohme, LLC ); MK-3475-D79 ( Registry Identifier: Merck, Sharp & Dohme, LLC )
• First Posted: October 14, 2020
• Last Update Posted: February 9, 2024
• Last Verified: February 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by PMV Pharmaceuticals, Inc:

PC14586; p53; Y220C; Phase 1; Phase 1/2; PMV; PMV Pharma; p53 mutation; TP53; TP53 mutation; p53 mutant; p53 reactivator; pembrolizumab; Keytruda; combination; PD-1; PD-L1; anti-PD-1; Merck; MSD; IgG4; mAb; Phase 1b; NGS; Next Generation Sequencing; precision; Phase 2; Rezatapopt

Additional relevant MeSH terms:

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