Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as PC14586
rezatapopt · 6 trials · 34 indications
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
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
Determine the Cmax of PC14586 when co-administered with itraconazole in plasma.
Determine the AUC0-inf of PC14586 when co-administered with itraconazole in plasma.
Determine the Tmax of PC14586 when co-administered with itraconazole in plasma.
Determine the AUC0-24 of PC14586 when co-administered with itraconazole in plasma.
Determine the AUC0-t of PC14586 when co-administered with itraconazole in plasma.
Determine the t1/2 of PC14586 when co-administered with itraconazole in plasma.
Determine the Cmax of PC14586 when co-administered with rabeprazole in plasma.
Determine the AUC0-last of PC14586 when co-administered with rabeprazole in plasma.
Determine the AUC0-inf of PC14586 when co-administered with rabeprazole in plasma.
Determine the Tmax of PC14586 when co-administered with rabeprazole in plasma.
Determine the Cmax of PC14586 when co-administered with famotidine in plasma.
Determine the AUC0-last of PC14586 when co-administered with famotidine in plasma.
Determine the AUC0-inf of PC14586 when co-administered with famotidine in plasma.
Determine the Tmax of PC14586 when co-administered with famotidine in plasma.
Determine Cmax for PC14586 and PC16163 in plasma.
Determine tmax for PC14586 and PC16163 in plasma.
Determine AUC0-inf for PC14586 and PC16163 in plasma.
Determine AUC0-t for PC14586 and PC16163 in plasma.
Determine t 1/2 for PC14586 and PC16163 in plasma.
Determine CL/F for PC14586 and PC16163 in plasma.
Determine Vd/F for PC14586 and PC16163 in plasma.
Determine total radioactivity for PC14586 and PC16163 in whole blood and plasma.
Determine total radioactivity of PC14586 excreted in feces
Determine half life of total radioactivity of PC14586 excreted in feces.
Determine the fraction excreted of total radioactivity of PC14586 in feces.
Determine half-life of fraction excreted of total radioactivity of PC14586 in feces.
Determine total radioactivity of PC14586 excreted in urine.
Determine half life of total radioactivity of PC14586 excreted in urine.
Determine the fraction excreted of total radioactivity of PC14586 in urine.
Determine half-life of fraction excreted of total radioactivity of PC14586 in urine.
Determine the renal clearance of PC14586 in urine.
| Arm | Type | Description |
|---|---|---|
| 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. |
| 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. |
| PC14586 and Itraconazole | EXPERIMENTAL | Healthy participants will receive a single, oral dose of PC14586 on day 1. On day 20, participants will receive BID oral doses of itraconazole. On days 21-22, participants will receive a single, oral dose of itraconazole. On day 23, participants will receive a single, oral dose of PC14586 and a single oral dose of itraconazole. On days 24-27, participants will receive a single, oral dose of itraconazole. |
| Part 1: PC14586 and rabeprazole | EXPERIMENTAL | Healthy participants will receive a single, oral dose of PC14586 on day 1. On days 11-13, participants will receive an oral daily dose of rabeprazole. On day 14, participants will receive a co-administration dose of rabeprazole and PC14586. Rabeprazole will be given 1 hour prior to PC14586. Participants will be given a low-fat meal 30 minutes prior to PC14586 dosing. |
| Part 2: PC14586 and famotidine | EXPERIMENTAL | Healthy participants will receive a single, oral dose of PC14586 on day 1. On days 11-13, participants will receive a twice daily, oral dose of famotidine. On day 14, participants will receive PC14586 two hours before a dose of famotidine. Participants will be given a low-fat meal 30 minutes prior to PC14586 dosing. |
| Single, oral dose of [14C]-PC14586 | EXPERIMENTAL | Healthy, male participants will receive a single, oral dose of \[14C\]-PC14586 |
| Part 1 Sequence A | EXPERIMENTAL | Period 1 will be fed, then washout, then Period 2 will be fasted. |
| Part 1 Sequence B | EXPERIMENTAL | Period 1 will be fasted, then washout, then Period 2 will be fed. |
| Part 2 Sequence C | EXPERIMENTAL | Period 1 will be fed, then washout, then Period 2 will be fasted. A different dose of PC14586 will be tested. |
| Part 2 Sequence D | EXPERIMENTAL | Period 1 will be fasted, then washout, then Period 2 will be fed. A different dose of PC14586 will be tested. |
| Part 2 Japanese Cohort | EXPERIMENTAL | 6 Japanese participants will be administered a single dose of PC14586. |
| Name | Type | Description |
|---|---|---|
| rezatapopt | DRUG | First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation. |
| pembrolizumab | DRUG | Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes. |
| 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 |
| PC14586 | DRUG | First-in-class, oral, small molecule p53 reactivator that is selective for the TP53 Y220C mutation. |
| Itraconazole | DRUG | Antifungal treatment that is a potent inhibitor of CYP3A4. |
| Rabeprazole | DRUG | Part 1: Daily oral dose of rabeprazole on days 11-14. |
| Famotidine | DRUG | Part 2: Twice daily oral dose of famotidine on days 11-13. Single, oral dose of famotidine on day 14. |
| [14C]-PC14586 | DRUG | Single, oral dose of \[14C\]-PC14586 |
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 an...
| Company | Ticker | Trials | Lead Phase | Drugs |
|---|---|---|---|---|
| Merck & Co., Inc. | MRK | 3 | PHASE2 | Pembrolizumab, Gardasil 9 |
| Incyte Corporation | INCY | 1 | PHASE2 | Retifanlimab |
| Novartis AG Sponsored ADR | NVS | 1 | PHASE1 | KFA115 |
| Iovance Biotherapeutics Inc | IOVA | 2 | PHASE2 | Aldesleukin |
| AstraZeneca PLC | AZN | 1 | - | Trastuzumab deruxtecan |
Rezatapopt is an investigational oral small molecule being studied for advanced solid tumors that harbor a TP53 Y220C mutation. It is being developed by PMV Pharmaceuticals, Inc. (ticker PMVP) and is currently in Phase 1 clinical development. It has received FDA Fast Track designation.
Rezatapopt targets the tumor suppressor protein p53, specifically the TP53 Y220C mutation. This mutation is a structural alteration that impairs p53 function, and rezatapopt is designed to bind to and restore activity to the mutated protein. It is a small molecule therapeutic.
Rezatapopt is being developed by PMV Pharmaceuticals, Inc., which trades under the ticker PMVP. The company is the sponsor of the clinical trials evaluating the drug in patients with advanced solid tumors harboring a TP53 Y220C mutation.
Rezatapopt is in Phase 1 clinical development. It is an investigational drug and has not been approved by the FDA. The Phase 1 program includes a study with an enrollment of 300 patients and a separate drug interaction study with 14 patients.
Rezatapopt is being evaluated in two Phase 1 trials. NCT04585750, known as the PYNNACLE study, is recruiting patients with advanced solid tumors harboring a TP53 Y220C mutation across multiple countries. NCT07372625 is a drug interaction study examining the effects of multiple doses of rezatapopt on metformin, rosuvastatin, repaglinide, and midazolam.
Yes, rezatapopt is also known as PC14586. The Phase 1 PYNNACLE trial is titled as an evaluation of PC14586 in patients with advanced solid tumors harboring a TP53 Y220C mutation, confirming that PC14586 and rezatapopt refer to the same investigational compound.