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

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.

Rezatapopt is a first-in-class, oral, small molecule p53 reactivator that is selective for the TP53 Y220C mutation.

The primary objective of Phase 2 Monotherapy is to evaluate the efficacy of rezatapopt at the Recommended Phase 2 Dose (RP2D) including the Overall Response Rate (ORR) in the Ovarian Cancer Cohort and the ORR across all cohorts as determined by blinded independent central review. Secondary objectives of Phase 2 are to characterize the safety, pharmacokinetic (PK) properties, quality of life, and other efficacy measures of PC14586 rezatapopt at the RP2D. Enrollment is open for the Phase 2 Monotherapy portion of the study.

The primary objective of Phase 1 Monotherapy is to establish the maximum tolerated dose (MTD) and RP2D of rezatapopt. Secondary objectives are to characterize the PK properties, safety and tolerability, and to assess preliminary efficacy including ORR. Enrollment into Phase 1 Monotherapy is complete.

The primary objective of Phase 1b Combination Therapy is to establish the MTD/RP2D of rezatapopt when administered in combination with pembrolizumab. Secondary objectives of Phase 1b Combination Therapy are to characterize PK, safety and tolerability, and to assess preliminary efficacy of rezatapopt when administered in combination with pembrolizumab, including ORR. Enrollment into Phase 1b Combination Therapy is complete.

Eligibility Criteria:
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