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)

Protocol # :
Advanced Solid Tumor
Advanced Malignant Neoplasm
Metastatic Cancer
Metastatic Solid Tumor
Lung Cancer
Ovarian Cancer
Endometrial Cancer
Prostate Cancer
Colorectal Cancer
Breast Cancer
Other Cancer
Locally Advanced
Head and Neck Cancer
Disease Sites
Healthy volunteer
Transplanted organ and tissue status, unspecified
Disease not specified
Gastroesophageal Junction
Other specified personal risk factors, not elsewhere classified
Lip, Oral Cavity and Pharynx
Small Intestine
Other Digestive Organ
Other Respiratory and Intrathoracic Organs
Bones and Joints
Soft Tissue
Mycosis Fungoides
Other Skin
Corpus Uteri
Other Female Genital
Other Male Genital
Urinary Bladder
Other Urinary
Eye and Orbit
Brain and Nervous System
Unknown Sites
Ill-Defined Sites
Other Endocrine System
Kaposi's Sarcoma
Melanoma, Skin
Principal Investigator
Parikh, Aparna, Raj
Site Research Nurses
Baldwin, Kayla
Channel, Kelly
Daley, Alycia
Scheffler, Erin, E.
Spriggs, Kristen
Sutcliffe, Shaun

Trial Description

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.

Eligibility Requirements

Inclusion Criteria:

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

- 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

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

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

- 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

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

- 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)