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)

This Phase 1/2 study will assess the safety, tolerability, and efficacy of multiple dose
levels of PC14586 (INN: rezatapopt) alone (monotherapy) and in combination with pembrolizumab
in participants with advanced solid tumors containing a TP53 Y220C mutation.

Inclusion Criteria:

- At least 18 years of age or 12 to 17 years of age after Safety Review Committee
approval.

- 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

- Measurable disease per RECIST v1.1 (Phase 2)

Additional Criteria for Inclusion in Phase 1b (PC14586 (INN: 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 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)