Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
rezatapopt · 2 trials · 32 indications
Geometric mean metformin peak concentration (Cmax) when administered with rezatapopt versus metformin alone.
Geometric mean rosuvastatin peak concentration (Cmax) when administered with rezatapopt versus rosuvastatin alone.
Geometric mean repaglinide peak concentration (Cmax) when administered with rezatapopt versus repaglinide alone
Geometric mean midazolam peak concentration (Cmax) when administered with rezatapopt versus midazolam alone
Geometric mean metformin area under the concentration-time curve from pre-dose (time 0) to t post-dose (AUC0-t) when administered with rezatapopt versus metformin alone
Geometric mean rosuvastatin area under the concentration-time curve from pre-dose (time 0) to t post-dose (AUC0-t) when administered with rezatapopt versus rosuvastatin alone
Geometric mean repaglinide area under the concentration-time curve from pre-dose (time 0) to t post-dose (AUC0-t) when administered with rezatapopt versus repaglinide alone
Geometric mean midazolam area under the concentration-time curve from pre-dose (time 0) to t post-dose (AUC0-t) when administered with rezatapopt versus midazolam alone
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of metformin
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rosuvastatin
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of repaglinide
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of midazolam
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of metformin
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rosuvastatin
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of metformin
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rosuvastatin
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of repaglinide
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of midazolam
Number of participants with treatment related adverse events
RP2D will be determined using available safety and pharmacokinetics and pharmacodynamics data
Incidence of dose limiting toxicities (DLTs) during the first 28 days of treatment with rezatapopt
Number of participants with treatment related adverse events
Incidence of dose limiting toxicities (DLTs) during the first 28 days of treatment with rezatapopt
RP2D will be determined using available safety and pharmacokinetics and pharmacodynamics data
Number of participants with treatment related adverse events
Overall response rate in accordance with Response Evaluation Criteria (RECIST) v.1.1 as assessed by independent review across all cohorts
Overall response rate in accordance with Response Evaluation Criteria (RECIST) v.1.1 as assessed by independent review in the ovarian cancer cohort
| Arm | Type | Description |
|---|---|---|
| Part A, Days 1-24 and Part B, Cycles 1-33 | EXPERIMENTAL | Patients will receive a cocktail of metformin and rosuvastatin after a morning meal on Day 1. Serial PK samples will be collected on Days 1-3. Days 2-5 will serv as a washout period. On Day 2, patients will receive a cocktail of repaglinide and midazolam. Serial PK samples will be collected on Days 2-3. Days 3-5 will serve as a washout period. On Days 6-21 patients will receive rezatapopt with serial PK samples taken on Days 6-7 and sparse PK on Day 14. On Day 22, patients will receive rezatapopt concurrently with a cocktail of metformin and rosuvastatin. Serial PK samples will be collected on Days 22-24. On Day 23, patients will receive rezatapopt concurrently with a cocktail of repaglinide and midazolam. Serial PK samples will be collected on Days 23-24. In Part B, patients will receive rezatapopt as 2000 mg PO QD in 21-day cycles through Cycle 33 (approximately 2 years) or until another discontinuation criterion is met. |
| Phase 1 Monotherapy Dose Escalation | EXPERIMENTAL | Multiple dose levels of daily oral 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 rezatapopt to recommend a Phase 2 dose (RP2D). |
| Phase 1b Combination Therapy Dose Escalation, Part 1 | EXPERIMENTAL | Multiple dose levels of daily oral 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 rezatapopt when administered in combination with pembrolizumab. |
| Phase 1b Combination Therapy Dose Expansion, PD(L)-1 naive patients | EXPERIMENTAL | 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. |
| Phase 1b Combination Therapy Dose Expansion, PD(L)-1 relapsed/refractory patients | EXPERIMENTAL | Additional (expansion of) participants will enroll at the RP2D of daily oral 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. |
| Phase 2 Monotherapy Dose Expansion, Ovarian Cancer Cohort | EXPERIMENTAL | 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. |
| Phase 2 Monotherapy Dose Expansion, Lung Cancer Cohort | EXPERIMENTAL | 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. |
| Phase 2 Monotherapy Dose Expansion, Breast Cancer Cohort | EXPERIMENTAL | 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. |
| Phase 2 Monotherapy Dose Expansion, Endometrial Cancer Cohort | EXPERIMENTAL | 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. |
| Phase 2 Monotherapy Dose Expansion, Other Solid Tumors Cohort | EXPERIMENTAL | 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. |
| Name | Type | Description |
|---|---|---|
| metformin hydrochloride 500 mg tablet | DRUG | 500-mg immediate release tablet PO |
| rosuvastatin 10 mg tablet | DRUG | 10-mg tablet PO |
| repaglinide 0.5 mg tablet | DRUG | 0.5-mg tablet PO |
| midazolam hydrochloride syrup | DRUG | 2 mg dose (5-mg/2.5 mL syrup) PO |
| rezatapopt | DRUG | 2000 mg dose (4 x 500-mg tablets) PO |
| pembrolizumab | DRUG | Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes. |
Inclusion Criteria: 1. Written informed consent 2. 18 years and older 3. ECOG performance status (PS) score of 0 or 1 4. Confirmed locally advanced or metastatic solid malignancy with a TP53 Y220C mutation identified through a tumor-tissue based (e.g., FoundationOneCDx, PathGroup, Caris WES, MSK IM...
| Company | Ticker | Trials | Lead Phase | Drugs |
|---|---|---|---|---|
| Merck & Co., Inc. | MRK | 2 | PHASE2 | pembrolizumab |
| Incyte Corporation | INCY | 1 | PHASE2 | Chemotherapy, Retifanlimab |
| Iovance Biotherapeutics Inc | IOVA | 2 | PHASE2 | E7 TCR-T cells, Aldesleukin |
| Novartis AG Sponsored ADR | NVS | 1 | PHASE1 | KFA115, pembrolizumab |
| AstraZeneca PLC | AZN | 1 | - | Trastuzumab deruxtecan |
Rezatapopt is an investigational small molecule being developed for patients with advanced solid tumors that harbor a TP53 Y220C mutation. It is being studied in cancers including lung, ovarian, endometrial, prostate, colorectal, breast, head and neck, and other advanced or metastatic solid tumors.
Rezatapopt targets the TP53 Y220C mutation, a specific genetic alteration in the p53 tumor suppressor gene. By targeting this mutation, the drug aims to address cancers driven by this particular TP53 defect in advanced solid tumors.
Rezatapopt is being developed by PMV Pharmaceuticals, Inc., a biopharmaceutical company traded on the Nasdaq under the ticker symbol PMVP. The company is conducting clinical trials to evaluate the drug in patients with TP53 Y220C-mutated advanced solid tumors.
Rezatapopt is in Phase 1 clinical development. It is an investigational drug and has not been approved by the FDA. The drug has received Orphan Drug and Fast Track designations from the FDA for its intended use in TP53 Y220C-mutated cancers.
Rezatapopt is being evaluated in two Phase 1 trials. NCT04585750, the PYNNACLE study, is assessing the drug in patients with advanced solid tumors harboring a TP53 Y220C mutation, with an enrollment of 300. NCT07372625 is studying the effects of multiple doses on the pharmacokinetics of metformin, rosuvastatin, repaglinide, and midazolam in the same patient population.
Rezatapopt is the same drug as PC14586. The earlier clinical trial NCT04585750 was titled 'The Evaluation of PC14586 in Patients With Advanced Solid Tumors Harboring a TP53 Y220C Mutation (PYNNACLE)', indicating that PC14586 is an alternative name for rezatapopt.