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.

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.

Inclusion criteria

• Written informed consent
• 18 years and older
• ECOG performance status (PS) score of 0 or 1
• 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
• 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)
• Adequate organ function
• Life expectancy ≥3 months as assessed by the Investigator

Exclusion criteria

• 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).
• 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
• 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
• 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.
• Stroke or transient ischemic attack within 6 months before screening
• 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
• Active gastrointestinal disease that may interfere significantly with the absorption, distribution, metabolism, or excretion of study drug
• History of prior organ transplant
• 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
• 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.
• Patients with a known KRAS single-nucleotide variation (SNV) mutation
• Major surgery (excluding placement of vascular access) within 4 weeks of first dose of study drugs

Other protocol-defined inclusion/exclusion criteria may apply