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

Phase 2RecruitingNCT04585750

PMV Pharmaceuticals, Inc300 enrolled

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.

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Interventions

rezatapoptDRUG

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

pembrolizumabDRUG

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

Eligibility

Sex: ALLMin age: 12 Years

Medical Language ↔ Plain English

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

Locations (75)

University of California Irvine Chao Family Comprehensive Cancer Center

Irvine, California, United States

RECRUITING

University of San Diego Moores Cancer Center

La Jolla, California, United States

NOT_YET_RECRUITING

UCLA Jonsson Comprehensive Cancer Center

Los Angeles, California, United States

RECRUITING

USC Norris Comprehensive Cancer Center

Los Angeles, California, United States

Outcomes

Primary Outcomes

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 Outcomes

Phase 1 Monotherapy: PK profile of rezatapopt - Peak concentration (Cmax)

Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt

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)

Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt

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)

Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt

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)

Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt

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)

Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt

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.

Blood plasma concentration

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

Central Contacts

PMV Pharma Clinical Study Information Center

CONTACT

(609) 235-4038 clinicaltrials@pmvpharma.com

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Rocky Mountain Cancer Center

Denver, Colorado, United States

RECRUITING

Yale Cancer Center

New Haven, Connecticut, United States

RECRUITING

Medical Oncology Hematology Consultants

Newark, Delaware, United States

RECRUITING

University of Miami - Sylvester Comprehensive Cancer Center

Miami, Florida, United States

RECRUITING

Advent Health

Orlando, Florida, United States

NOT_YET_RECRUITING

Florida Cancer Specialists South

Port Charlotte, Florida, United States

RECRUITING

...and 65 more locations

Phase 1 Monotherapy (Dose Escalation): Overall Response Rate per RECIST v1.1 or PCWG3 modified RECIST v1.1

Evaluation of preliminary anti-tumor activity of rezatapopt as a single agent

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

Evaluation of preliminary anti-tumor activity of rezatapopt as a single agent

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

Evaluation of preliminary anti-tumor activity of rezatapopt as a single agent

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

Evaluation of preliminary anti-tumor activity of rezatapopt as a single agent

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

Evaluation of preliminary anti-tumor activity of rezatapopt as a single agent

Time frame: 41 months for study (end of Phase 1)

Phase 1 Monotherapy (Dose Escalation): Overall Survival

Evaluation of preliminary anti-tumor activity of rezatapopt as a single agent

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)

Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt

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)

Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt

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)

Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt

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)

Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt

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)

Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt

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.

Blood plasma concentration

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

Evaluation of anti-tumor activity of rezatapopt in combination with pembrolizumab

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

Evaluation of anti-tumor activity of rezatapopt in combination with pembrolizumab

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

Evaluation of anti-tumor activity of rezatapopt in combination with pembrolizumab

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

Evaluation of anti-tumor activity of rezatapopt in combination with pembrolizumab

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

Phase 1b Combination Therapy: Overall Survival

Evaluation of anti-tumor activity of rezatapopt in combination with pembrolizumab

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

Number of participants with treatment related adverse events

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

Evaluation of anti-tumor activity of rezatapopt in combination with pembrolizumab

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

Phase 2 Monotherapy: PK profile of rezatapopt - Time of peak concentration (Tmax)

Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt

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)

Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt

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)

Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt

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)

Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt

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)

Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt

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.

Blood plasma concentration

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

Number of participants with treatment related adverse events

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

Evaluation of anti-tumor activity of rezatapopt as a single agent

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

Evaluation of anti-tumor activity of rezatapopt as a single agent

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

Evaluation of anti-tumor activity of rezatapopt as a single agent

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

Evaluation of anti-tumor activity of rezatapopt as a single agent

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

Evaluation of anti-tumor activity of rezatapopt as a single agent

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

Evaluation of anti-tumor activity of rezatapopt as a single agent

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

Evaluation of anti-tumor activity of rezatapopt as a single agent

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

Evaluation of anti-tumor activity of rezatapopt as a single agent

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

Evaluation of anti-tumor activity of rezatapopt as a single agent

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

Evaluation of anti-tumor activity of rezatapopt as a single agent

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

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

Evaluation of anti-tumor activity of rezatapopt as a single agent

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

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

Evaluation of anti-tumor activity of rezatapopt as a single agent

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

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

Changes from baseline in quality of life as measured by a validated instrument, for participants 18 and older

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

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

Overview

Conditions

Interventions

Eligibility

Locations (75)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts