Advanced Malignant Neoplasm, Advanced Solid Tumor, Breast Cancer, Colorectal Cancer, Endometrial Cancer, ER/PR(+), Her2(-) Breast Cancer, ER/PR Positive Breast Cancer, Gall Bladder Cancer, Head and Neck Cancer, HER2- Breast Cancer, HER2+ Breast Cancer, HER2-negative Breast Cancer, HER2-positive Breast Cancer, Locally Advanced, Lung Cancer, Metastatic Cancer, Metastatic Solid Tumor, Non-Small Cell Lung Cancer, Non-Small Cell Lung Carcinoma, NSCLC, NSCLC (Non-small Cell Lung Cancer), Other Cancer, Ovarian Cancer, Prostate Cancer, SCLC, Small Cell Lung Cancer, Small Cell Lung Cancer ( SCLC ), Small Cell Lung Carcinoma, TNBC, Triple Negative Breast Cancer
Conditions
Keywords
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
Brief 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.
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.
Sponsors
PMV Pharmaceuticals, Inc
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
During Phase 2 Monotherapy, 2000mg QD of PC14586 (INN: rezatapopt) 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. Enrollment ongoing. 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. Enrollment closed. During Part 1 of the Ph 1b Combination Therapy, patients will be assigned a dose level using mTPI design. A recommended 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. Enrollment closed.
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 Monotherapy (Dose Escalation): Determine the number and type of adverse events to characterize the safety of rezatapopt | 40 months | Number of participants with treatment related adverse events |
| Phase 1 Monotherapy (Dose Escalation): Establish the Recommended Phase 2 Dose (RP2D) | 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) | The first 28 days of treatment (Cycle 1) per patient | Incidence of dose limiting toxicities (DLTs) during the first 28 days of treatment with rezatapopt |
| 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 | 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 rezatapopt when administered in combination with pembrolizumab | 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 rezatapopt |
| Phase 1b Combination Therapy (Part 1: Dose Escalation): Establish the Recommended Phase 2 Dose (RP2D) of rezatapopt when administered in combination with pembrolizumab | 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 rezatapopt when administered in combination with pembrolizumab | 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 rezatapopt | 34 months | Overall response rate in accordance with Response Evaluation Criteria (RECIST) v.1.1 as assessed by independent review across all cohorts |
| Phase 2 Monotherapy (Dose Expansion): Response rate assessment to evaluate the clinical activity / efficacy of rezatapopt in ovarian cancer patients | 34 months | Overall response rate in accordance with Response Evaluation Criteria (RECIST) v.1.1 as assessed by independent review in the ovarian cancer cohort |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 Monotherapy: PK profile of rezatapopt - Peak concentration (Cmax) | 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 rezatapopt |
| Phase 1 Monotherapy: PK profile of rezatapopt - Time of peak concentration (Tmax) | 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 rezatapopt |
| 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) | 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 rezatapopt |
| Phase 1 Monotherapy: PK profile of rezatapopt - Area under the plasma concentration-time curve in one dosing interval (AUCtau) | 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 rezatapopt |
| Phase 1 Monotherapy: PK profile of rezatapopt - Trough observed concentrations (Ctrough/Ctau) | 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 rezatapopt |
| Phase 1 Monotherapy: Blood plasma assessment to describe the concentration of PC14586 and metabolites when rezatapopt is administered orally. | 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 | 41 months for study (end of Phase 1) | Evaluation of preliminary anti-tumor activity of rezatapopt as a single agent |
| Phase 1 Monotherapy (Dose Escalation): Time to Response per RECIST v1.1 or PCWG3 modified RECIST v1.1 | 41 months for study (end of Phase 1) | Evaluation of preliminary anti-tumor activity of rezatapopt as a single agent |
| Phase 1 Monotherapy (Dose Escalation): Duration of Response per RECIST v1.1 or PCWG3 modified RECIST v1.1 | 41 months for study (end of Phase 1) | Evaluation of preliminary anti-tumor activity of rezatapopt as a single agent |
| Phase 1 Monotherapy (Dose Escalation): Disease Control Rate per RECIST v1.1 or PCWG3 modified RECIST v1.1 | 41 months for study (end of Phase 1) | Evaluation of preliminary anti-tumor activity of rezatapopt as a single agent |
| Phase 1 Monotherapy (Dose Escalation): Progression Free Survival per RECIST v1.1 or PCWG3 modified RECIST v1.1 | 41 months for study (end of Phase 1) | Evaluation of preliminary anti-tumor activity of rezatapopt as a single agent |
| Phase 1 Monotherapy (Dose Escalation): Overall Survival | 41 months for study (end of Phase 1) | Evaluation of preliminary anti-tumor activity of rezatapopt as a single agent |
| Phase 1b Combination Therapy: PK profile of rezatapopt in combination with pembrolizumab - Peak concentration (Cmax) | Approximately 12 months per patient (30 months for treatment arm) | Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt |
| Phase 1b Combination Therapy: PK profile of rezatapopt in combination with pembrolizumab - Time of peak concentration (Tmax) | Approximately 12 months per patient (30 months for treatment arm) | Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt |
| 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) | Approximately 12 months per patient (30 months for treatment arm) | Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt |
| Phase 1b Combination Therapy: PK profile of rezatapopt in combination with pembrolizumab - Area under the plasma concentration-time curve in one dosing interval (AUCtau) | Approximately 12 months per patient (30 months for treatment arm) | Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt |
| Phase 1b Combination Therapy: PK profile of rezatapopt in combination with pembrolizumab - Trough observed concentrations (Ctrough/Ctau) | Approximately 12 months per patient (30 months for treatment arm) | Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt |
| Phase 1b Combination Therapy: Blood plasma assessment to describe the concentration of rezatapopt and metabolites when rezatapopt is administered orally in combination with pembrolizumab. | 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 | 30 months for study (end of Phase 1b) | Evaluation of anti-tumor activity of 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 | 30 months for study (end of Phase 1b) | Evaluation of anti-tumor activity of 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 | 30 months for study (end of Phase 1b) | Evaluation of anti-tumor activity of 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 | 30 months for study (end of Phase 1b) | Evaluation of anti-tumor activity of rezatapopt in combination with pembrolizumab |
| Phase 1b Combination Therapy: Overall Survival | 30 months for study (end of Phase 1b) | Evaluation of anti-tumor activity of rezatapopt in combination with pembrolizumab |
| Phase 1b Combination Therapy: Determine the number and type of adverse events to characterize the safety of rezatapopt | 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 | 30 months for study (end of Phase 1b) | Evaluation of anti-tumor activity of rezatapopt in combination with pembrolizumab |
| Phase 2 Monotherapy: PK profile of rezatapopt - Time of peak concentration (Tmax) | 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 rezatapopt |
| Phase 2 Monotherapy: PK profile of rezatapopt - Peak concentration (Cmax) | 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 rezatapopt |
| 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) | 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 rezatapopt |
| Phase 2 Monotherapy: PK profile of rezatapopt - Area under the plasma concentration-time curve in one dosing interval (AUCtau) | 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 rezatapopt |
| Phase 2 Monotherapy: PK profile of rezatapopt - Trough observed concentrations (Ctrough/Ctau) | 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 rezatapopt |
| Phase 2 Monotherapy: Blood plasma assessment to describe the concentration of rezatapopt and metabolites when rezatapopt is administered orally. | 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 rezatapopt | 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 | 34 months for study (end of Phase 2) | Evaluation of anti-tumor activity of 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 | 34 months for study (end of Phase 2) | Evaluation of anti-tumor activity of 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 | 34 months for study (end of Phase 2) | Evaluation of anti-tumor activity of 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 | 34 months for study (end of Phase 2) | Evaluation of anti-tumor activity of 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 | 34 months for study (end of Phase 2) | Evaluation of anti-tumor activity of 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 | 34 months for study (end of Phase 2) | Evaluation of anti-tumor activity of 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 | 34 months for study (end of Phase 2) | Evaluation of anti-tumor activity of 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 | 34 months for study (end of Phase 2) | Evaluation of anti-tumor activity of 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 | 34 months for study (end of Phase 2) | Evaluation of anti-tumor activity of 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 | 34 months for study (end of Phase 2) | Evaluation of anti-tumor activity of rezatapopt as a single agent |
| Phase 2 Monotherapy (Dose Expansion): Overall Survival in ovarian cancer cohort | 34 months for study (end of Phase 2) | Evaluation of anti-tumor activity of rezatapopt as a single agent |
| Phase 2 Monotherapy (Dose Expansion): Overall Survival across all cohorts | 34 months for study (end of Phase 2) | Evaluation of anti-tumor activity of rezatapopt as a single agent |
| Phase 2 Monotherapy (Dose Expansion): Quality of life assessment | 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 |
Countries
Australia, France, Germany, Italy, Singapore, South Korea, Spain, United Kingdom, United States
Contacts
CONTACTPMV Pharma Clinical Study Information Center
STUDY_DIRECTORMarc Fellous, MD
Sr. Vice President of Medical Affairs
Outcome results
None listed