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

About

Brief Summary

The Phase 2 monotherapy portion of this study is currently enrolling and will evaluate the efficacy and safety of PC14586 (INN rezatapopt) in participants with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation. The Phase 1 portion of the study will assess the safety, tolerability and preliminary efficacy of multiple dose levels of rezatapopt as monotherapy and in Phase 1b in combination with pembrolizumab.

Primary Purpose

Treatment

Study Type

Interventional

Phase

Phase 1/Phase 2

Eligibility

Gender

All

Healthy Volunteers

No

Minimum Age

12 Years

Maximum Age

N/A

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 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 inducers
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