PYNNACLE: This study is assessing how safe, tolerable and effective multiple dose levels of a drug called PC14586 are when given alone or in combination with immunotherapy in people with advanced solid cancers containing a TP53 Y220C mutationA Phase 1/2 Open-label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of PC14586 in Patients With Locally Advanced or Metastatic Solid Tumors Harboring a TP53 Y220C Mutation

Exclusion

• 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 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

Additional Criteria for Exclusion from Phase 2 (PC14586 monotherapy)

• Known KRAS mutation, defined as a single nucleotide variant (SNV) (Phase 2)

Additional Criteria for Exclusion from Phase 1b (PC14586 (INN: rezatapopt) + pembrolizumab combination)

• 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 PC14586 (INN: rezatapopt)