A Phase 1/2 Open-label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of PC14586 in Patients With Advanced Solid Tumors Harboring a p53 Y220C Mutation (PYNNACLE)

PC14586 is a first-in-class, oral, small molecule p53 reactivator that is selective for the TP53 Y220C mutation. The trial will be conducted in 2 parts: dose escalation (Phase 1) and dose expansion (Phase 2).

The primary objective of Phase 1 is to establish the maximum tolerated dose / recommended dose of PC14586 to treat participants with advanced solid tumors harboring a TP53 Y220C mutation. Secondary objectives of Phase 1 are to characterize the pharmacokinetic properties of the investigational drug, its safety and tolerability, and to assess preliminary efficacy of PC14586 including overall response rate (ORR).

The primary objective of Phase 2 is to assess the ORR in participants with advanced solid tumors harboring a TP53 Y220C mutation as determined by blinded independent central review. Secondary objectives of Phase 2 include the safety, pharmacokinetic properties, quality of life, and other efficacy measures of PC14586 at the recommended dose.

Inclusion Criteria:

• At least 18 years of age or 12 to 17 years of age after adequate adult safety data become available
• Advanced 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

Exclusion Criteria:

• Anti-cancer therapy within 21 days (or 5 half-lives) of receiving the study drug
• Radiotherapy within 28 days of receiving the study drug
• Primary CNS tumor (Phase 1, Phase 2 Cohort A)
• History of leptomeningeal disease or spinal cord compression
• Brain metastases, unless neurologically stable and do not require steroids to treat associated neurological symptom
• Stroke or transient ischemic attack within 6 months prior to screening
• Heart conditions such as unstable angina, uncontrolled hypertension, a heart attack within 6 months prior to screening, congestive heart failure, prolongation of QT interval, or other rhythm abnormalities
• Strong CYP3A4 inhibitors or inducers, medications with a known risk of QT/QTc prolongation, or proton pump inhibitors
• 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