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 Committeeapproval.

• 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 progressivedisease

• 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 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 treatassociated neurological symptoms

• Stroke or transient ischemic attack within 6 months prior to screening

• Heart conditions such as unstable angina, uncontrolled hypertension, a heart attackwithin 6 months prior to screening, congestive heart failure, prolongation of QTinterval, or other rhythm abnormalities

• Strong CYP3A4 inducers

• History of gastrointestinal (GI) disease that may interfere with absorption of studydrug or patients unable to take oral medication

• History of prior organ transplant

• Known, active malignancy, except for treated cervical intraepithelial neoplasia, ornon-melanoma skin cancer

• Known, active uncontrolled Hepatitis B, Hepatitis C, or human immunodeficiency virusinfection

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 anagent directed to another stimulatory or co-inhibitory T-cell receptor anddiscontinued 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 ofstudy intervention

• Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy within 7days 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 thatrequired steroids

• Active infection requiring systemic therapy

• Known history of HIV infection

• Has previously received rezatapopt