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 study will assess the safety, tolerability, and efficacy of multiple dose levels of
PC14586 alone and in combination with pembrolizumab in participants with advanced solid
tumors containing a TP53 Y220C mutation.
- At least 18 years of age or 12 to 17 years of age after adequate adult safety data
- 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
- Adequate organ function
Additional Criteria for Inclusion in Phase 1b (PC14586 + pembrolizumab combination)
- 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 (Phase 1, Phase 2 Cohort A)
- History of leptomeningeal disease or spinal cord compression
- Brain metastases, unless neurologically stable and do not require steroids to treat
associated neurological symptom
- 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
Additional Criteria for Exclusion from Phase 1b (PC14586 + 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
- 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
- Active infection requiring systemic therapy.
- Known history of HIV infection.