A Study to Investigate the Effects of Multiple Doses of Rezatapopt on the Pharmacokinetics of Metformin, Rosuvastatin, Repaglinide, and Midazolam in Patients With Advanced Solid Tumors Harboring a TP53 Y220C Mutation.

A Phase 1, Open-label, 2-part, Drug-Drug Interaction Study to Evaluate the Effects of Multiple Oral Doses of Rezatapopt on the Pharmacokinetics of Metformin, Rosuvastatin, Repaglinide, and Midazolam in Patients With Advanced Solid Tumors Harboring a TP53 Y220C Mutation.

This study aims to evaluate the effects of rezatapopt on the pharmacokinetics of metformin, rosuvastatin, repaglinide, and midazolam in patients with advanced solid tumors harboring a TP53 Y220C mutation.

Study Overview

• Status: Recruiting
• Conditions: Advanced Solid Tumors; TP53 Y220C Mutation
• Intervention / Treatment: Drug: metformin hydrochloride 500 mg tablet; Drug: rosuvastatin 10 mg tablet; Drug: repaglinide 0.5 mg tablet; Drug: midazolam hydrochloride syrup; Drug: rezatapopt

Detailed Description

Rezatapopt (PC14586) is a first-in-class oral, small molecule p53 reactivator that is selective for the TP53 Y220C mutation.

This Phase 1, open-label, drug-drug interaction study will investigate the effect of multiple oral doses of rezatapopt on the pharmacokinetics (PK) of metformin, rosuvastatin, repaglinide, and midazolam in patients with advanced solid tumors harboring a TP53 Y220C mutation. This study will consist of 2 parts, Part A and Part B.

Part A is a 24-day drug-drug interaction (DDI) portion that follows a fixed- sequence design, including a screening period and 2 treatment periods.

In Treatment Period 1 patients will receive metformin and rosuvastatin, followed by repaglinide and midazolam. Patients will not receive rezatapopt during Treatment Period 1.

Following washout, in Treatment Period 2 which will begin on Day 6, patients will receive 2000 mg rezatapopt administered orally once daily along with metformin and rosuvastatin, and then repaglinide and midazolam in accordance with the fixed-sequence dosing schedule. Serial PK samples will be collected on designated days throughout Part A.

Patients who complete Part A without suspected disease progression and unacceptable toxicity or another discontinuation criterion and who are deemed likely to continue benefiting from the study treatment, will be allowed to continue treatment with rezatapopt in Part B.

In Part B, patients will receive 2000 mg rezatapopt orally daily in 21-day cycles, up to Cycle 33 (approximately 2 years of rezatapopt treatment, inclusive of Part A) or until another discontinuation criterion is met.

A maximum of approximately 14 patients are planned to enroll in this study.

• Study Type: Interventional
• Enrollment (Estimated): 14
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: PMV Pharma Clinical Study Information Center; Phone Number: 609-235-4038; Email: clinicaltrials@pmvpharma.com
• Study Contact Backup: Name: SCRI Medical Support Center; Phone Number: 1-615-329-7286; Email: SCRI.InnovationsMedical@scri.com

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80237
      • Recruiting
      • HealthOne Denver
      • Contact: Email: scri.refmal1199@scri.com
  • Florida
    • Orlando, Florida, United States, 32827
      • Recruiting
      • Florida Cancer Specialists
      • Contact: Email: scri.refmal1199@scri.com
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • SCRI Oncology Partners
      • Contact: Email: scri.refmal1199@scri.com
  • Texas
    • Dallas, Texas, United States, 75230
      • Recruiting
      • SCRI at Mary Crowley
      • Contact: Email: scri.refmal1199@scri.com
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • NEXT Oncology
      • Contact: Email: scri.refmal1199@scri.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 IMPACT, TEMPUS) or a liquid-biopsy based (e.g., Caris, MSK Access) NGS molecular test.

   - Patients with primary CNS tumors are allowed to enroll

5. Patients with castration-resistant prostate cancer must have ongoing androgen deprivation therapy with a gonadotropin-releasing hormone analog or inhibitor or orchiectomy (medical or surgical castration)
6. Adequate organ function
7. Life expectancy ≥3 months as assessed by the Investigator

Exclusion Criteria:

1. Patients with ovarian, breast, lung, or endometrial tumors who are eligible for the PYNNACLE Phase 2 trial (NCT04585750), unless the corresponding cohort in the PYNNACLE trial is closed to enrollment at the time of screening (to avoid overlap with that study).

2. Treatment, food, or drink with any of the following:

   • Any systemic anticancer therapies, including but not limited to chemotherapy, small molecule, biologic, or hormonal agents from a previous treatment regimen, or investigational anticancer agents from clinical study within 21 days or 5 half-lives (whichever is longer) prior to the first dose of study drugs
   • Radiotherapy within 14 days of first dose of study drugs. Palliative radiotherapy particularly limited field and stereotactic body radiation therapy to non-target lesions should be allowed.
   • Inhibitors or inducers of the enzymes and transporters being tested in this study within 14 days of starting study drugs
   • Sensitive substrates of CYP3A4 or CYP2C8 with a narrow therapeutic index within 14 days of starting study drugs
   • Herbal preparations/medications known to be strong or moderate CYP3A4 inhibitors or inducers or to have other significant potential for interaction with rezatapopt within 14 days of starting study drugs
   • Foods or drinks with CYP3A inhibition potential (e.g., grapefruit, grapefruit juice, Seville orange juice, pomelos, starfruits) within 14 days of starting study drugs
3. Known or suspected significant hypersensitivity, intolerance, or allergy to rezatapopt, metformin, rosuvastatin, repaglinide, or midazolam or any of their excipients or medicinal products with similar chemical structures, food, or other substances
4. Previously untreated brain metastases, leptomeningeal metastases, or spinal cord compression due to disease. Patients who have received radiation or surgery for brain metastases are eligible if therapy was completed at least 4 weeks prior to starting study drugs, there is no evidence of central nervous system disease progression or mild neurologic symptoms, and there is no requirement for chronic corticosteroid therapy.
5. Stroke or transient ischemic attack within 6 months before screening

6. Clinically significant, uncontrolled heart diseases currently or within the last 6 months including:

   • QTcF >470 msec obtained as the mean from 3 consecutive resting ECGs. A QTcF value corrected for wide QRS >120 msec (QTcFBBB) should be used in place of QTcF for patients with non-clinically significant wide QRS >120 msec due to a pacemaker or bundle branch block.
   • Uncontrolled hypertension
7. Active gastrointestinal disease that may interfere significantly with the absorption, distribution, metabolism, or excretion of study drug
8. History of prior organ transplant
9. Presence of other active invasive cancers other than the one treated in this study within 2 years prior to screening, except appropriately treated basal cell carcinoma of the skin, in situ carcinoma of the uterine cervix, or other local tumors considered cured by local treatment
10. Known, active, uncontrolled hepatitis B virus infection (i.e., viral load above the limit of quantification), hepatitis C virus infection (i.e., viral load above the limit of quantification), or human immunodeficiency virus infection (viral load >400 copies/mL of blood). Patients whose viral load is controlled should be on established antiretroviral therapy for at least 4 weeks before receiving their first dose of study drugs.
11. Patients with a known KRAS single-nucleotide variation (SNV) mutation
12. Major surgery (excluding placement of vascular access) within 4 weeks of first dose of study drugs

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Part A, Days 1-24 and Part B, Cycles 1-33; 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.

Drug: metformin hydrochloride 500 mg tablet; 500-mg immediate release tablet PO; Drug: rosuvastatin 10 mg tablet; 10-mg tablet PO; Drug: repaglinide 0.5 mg tablet; 0.5-mg tablet PO; Drug: midazolam hydrochloride syrup; 2 mg dose (5-mg/2.5 mL syrup) PO; Drug: rezatapopt; 2000 mg dose (4 x 500-mg tablets) PO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Metformin Cmax geometric mean ratio	Geometric mean metformin peak concentration (Cmax) when administered with rezatapopt versus metformin alone.	Day 1 to Day 24 of Part A
Rosuvastatin Cmax geometric mean ratio	Geometric mean rosuvastatin peak concentration (Cmax) when administered with rezatapopt versus rosuvastatin alone.	Day 1 to Day 24 of Part A
Repaglinide Cmax geometric mean ratio	Geometric mean repaglinide peak concentration (Cmax) when administered with rezatapopt versus repaglinide alone	Day 1 to Day 24 of Part A
Midazolam Cmax geometric mean ratio	Geometric mean midazolam peak concentration (Cmax) when administered with rezatapopt versus midazolam alone	Day 1 to Day 24 of Part A
Metformin AUC0-t geometric mean ratio	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	Day 1 to Day 24 of Part A
Rosuvastatin AUC0-t geometric mean ratio	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	Day 1 to Day 24 of Part A
Repaglinide AUC0-t geometric mean ratio	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	Day 1 to Day 24 of Part A
Midazolam AUC0-t geometric mean ratio	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	Day 1 to Day 24 of Part A
PK profile of metformin - area under the concentration-time curve from pre-dose (time 0) to 24 h post-dose (AUC0-24)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of metformin	Day 1 to Day 24 of Part A
PK profile of rosuvastatin - area under the concentration-time curve from pre-dose (time 0) to 24 h post-dose (AUC0-24)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rosuvastatin	Day 1 to Day 24 of Part A
PK profile of repaglinide - area under the concentration-time curve from pre-dose (time 0) to 24 h post-dose (AUC0-24)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of repaglinide	Day 1 to Day 24 of Part A
PK profile of midazolam - area under the concentration-time curve from pre-dose (time 0) to the time 24 h post-dose (AUC0-24)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of midazolam	Day 1 to Day 24 of Part A
PK profile of metformin - area under the concentration-time curve from pre-dose (time 0) to 48 h post-dose (AUC0-48)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of metformin	Day 1 to Day 24 of Part A
PK profile of rosuvastatin - area under the concentration-time curve from pre-dose (time 0) to 48 h post-dose (AUC0-48)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rosuvastatin	Day 1 to Day 24 of Part A
PK Profile of Metformin - Time of Peak Concentration (Tmax)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of metformin	Day 1 to Day 24 of Part A
PK Profile of Rosuvastatin - Time of Peak Concentration (Tmax)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rosuvastatin	Day 1 to Day 24 of Part A
PK Profile of Repaglinide - Time of Peak Concentration (Tmax)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of repaglinide	Day 1 to Day 24 of Part A
PK Profile of Midazolam - Time of Peak Concentration (Tmax)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of midazolam	Day 1 to Day 24 of Part A

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the incidence and severity of adverse events to characterize the safety of rezatapopt alone or co-administered with metformin and rosuvastatin, or repaglinide and midazolam	Number of participants with adverse events, with severity assessed using CTCAE v5.0	From Day 6 to 24 of Part A
Assess the safety and tolerability of multiple doses of rezatapopt alone or co-administered with metformin and rosuvastatin, or repaglinide and midazolam	Changes from baseline of physical examinations.	Day 6 to 24 of Part A.
Assess the safety and tolerability of multiple doses of rezatapopt alone or co-administered with metformin and rosuvastatin, or repaglinide and midazolam	Changes from baseline of vital signs	Day 6 to Day 24 of Part A
Assess the safety and tolerability of multiple doses of rezatapopt alone or co-administered with metformin and rosuvastatin, or repaglinide and midazolam	Changes from baseline of clinical laboratory values	Day 6 to Day 24 of Part A
Assess the safety and tolerability of multiple doses of rezatapopt alone or co-administered with metformin and rosuvastatin, or repaglinide and midazolam	Changes from baseline of 12 lead triplicate ECGs (electrocardiogram)	Day 6 to Day 24 of Part A
Assess the safety and tolerability of multiple doses of rezatapopt alone or co-administered with metformin and rosuvastatin, or repaglinide and midazolam	Changes in baseline of Eastern Cooperative Oncology Group Performance Status (ECoG) using a scale of 0-5	Day 6 to Day 24 of Part A
PK profile of rezatapopt and its metabolites, M13 and M14 - peak concentration (Cmax)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt and its metabolites, M13 and M14.	Day 6 to Day 24 of Part A
PK profile of rezatapopt and its metabolites, M13 and M14 - area under the concentration-time curve from pre-dose (time 0) to the time t post-dose (AUC0-t)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt and its metabolites, M13 and M14.	Day 6 to Day 24 of Part A
PK profile of rezatapopt and its metabolites, M13 and M14 - time of peak concentration (Tmax)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt and its metabolites, M13 and M14.	Day 6 to Day 24 of Part A
PK profile of rezatapopt and its metabolites, M13 and M14 - area under the concentration-time curve from pre-dose (time 0) to the time 24 h post-dose (AUC0-24)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rezatapopt and its metabolites, M13 and M14.	Day 6 to Day 24 of Part A

Collaborators and Investigators

• Sponsor: PMV Pharmaceuticals, Inc
• Collaborators: SCRI Development Innovations, LLC
• Investigators: Study Chair: Vivek Subbiah, MD, SCRI

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2026
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): January 1, 2028

Study Registration Dates

• First Submitted: January 5, 2026
• First Submitted That Met QC Criteria: January 20, 2026
• First Posted (Actual): January 28, 2026

Study Record Updates

• Last Update Posted (Actual): March 12, 2026
• Last Update Submitted That Met QC Criteria: March 10, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: midazolam; Phase 1; metformin; rosuvastatin; DDI; PC14586; Y220C; PMV; PMV Pharma; repaglinide; rezatapopt
• Additional Relevant MeSH Terms: Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pharmaceutical Preparations; Dosage Forms; Hydrocarbons; Amides; Pyrimidines; Hydrocarbons, Halogenated; Biguanides; Guanidines; Amidines; Sulfonamides; Sulfones; Fluorobenzenes; Hydrocarbons, Fluorinated; Rosuvastatin Calcium; Metformin; Tablets; repaglinide
• Other Study ID Numbers: PMV-586-106

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No