The Evaluation of PC14586 in Patients with Advanced Solid Tumors Harboring a TP53 Y220C Mutation (PYNNACLE)

Eligibility 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 anticancer therapy and progressive disease
• * Adequate organ function
• * Measurable disease per RECIST v1.1 (Phase 2)
• * Anti-PD-1/PD-L1 naive or must have progressed on treatment
• * Measurable disease
• * 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
• * History of leptomeningeal disease or spinal cord compression
• * Brain metastases, unless neurologically stable and do not require steroids to treat associated neurological symptoms
• * 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 inducers
• * 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
• * Known KRAS mutation, defined as a single nucleotide variant (SNV) (Phase 2)
• * Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor and discontinued from that treatment due to a Grade 3 or higher immune-related AE (irAE)
• * Received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention
• * Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy within 7 days prior to the first dose of study drug
• * Hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients
• * Active autoimmune disease that has required systemic treatment in past 2 years
• * History of radiation pneumonitis
• * History of (non-infectious) or active pneumonitis / interstitial lung disease that required steroids
• * Active infection requiring systemic therapy
• * Known history of HIV infection
• * Has previously received rezatapopt