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

Inclusion 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)

Additional Criteria for Inclusion in Phase 1b (rezatapopt) + pembrolizumab combination)

* Anti-PD-1/PD-L1 naive or must have progressed on treatment
* Measurable disease

Exclusion Criteria:

* Anti-cancer therapy within 21 days (or 5 half-lives) of receiving the study drug
* Radiotherapy within 14 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 within 6 months prior to screening, 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 and strong CYP2C9 inhibitors/inducers within 14 days of first dose of rezatapopt
* 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 (rezatapopt monotherapy)

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

Additional Criteria for Exclusion from Phase 1b (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 rezatapopt