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Ref Type Abstract
PMID
Authors Ecaterina Elena Dumbrava, Melissa Lynne Johnson, Anthony W. Tolcher, Geoffrey Shapiro, John A. Thompson, Anthony B. El-Khoueiry, Andrae Lavon Vandross, Shivaani Kummar, Aparna Raj Parikh, Pamela N. Munster, Erika Daly, Laura De Leon, Megan Khaddar, Kimberley LeDuke, Kimberly Robell, Lisa Iacono Sheehan, Meagen St. Louis, Amy Wiebesiek, Leila Alland, Alison M. Schram
Title First-in-human study of PC14586, a small molecule structural corrector of Y220C mutant p53, in patients with advanced solid tumors harboring a TP53 Y220C mutation.
Journal Journal of Clinical Oncology
Vol 40
Issue 16_suppl
Date June 2, 2022
URL https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.3003
Abstract Text 3003. Background: The p53 tumor suppressor protein is a transcription factor that acts to maintain genome stability in response to cellular stress. Spontaneous mutation of the TP53 gene leading to inactivation of the p53 protein is the most common mutational event across all human cancers. PC14586 is a novel, small molecule structural corrector that binds selectively to p53 Y220C mutant protein and restores the p53 wildtype conformation and transcriptional activity, resulting in potent preclinical antitumor activity. This Phase 1 multicenter dose escalation study assesses PC14586 safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy in patients (pts) with advanced solid tumors that harbor the TP53 Y220C mutation. Methods: Eligible adult pts with locally advanced or metastastic TP53 Y220C mutant solid tumors received increasing doses of oral PC14586 using the modified Toxicity Probability Interval design to estimate toxicity and to determine maximum tolerated dose and recommended phase 2 dose. Plasma PK was characterized using standard methods. Preliminary efficacy was assessed by RECIST v1.1. Reporting of interim results was approved by the study’s Safety Review Committee. Results: As of 08 Feb 2022, 29 pts (62% female, median age 62 years) with a variety of TP53 Y220C mutant solid tumor types (median number of prior lines of therapy 3; range 1 to 8) were treated in 7 dose cohorts of PC14586: 150 mg QD (3 pts), 300 mg QD (3 pts), 600 mg QD (4 pts), 1150 mg QD (5 pts), 2000 mg QD (7 pts), 2500 mg QD (4 pts) and 1500 mg BID (3 pts). PC14586 was generally well-tolerated; treatment-related AEs were observed in 79% of pts that were all Grade 1/2 in severity except 2 Grade 3 AEs (alanine aminotransferase increased and neutrophil count decreased). The most common AEs (≥15% of pts) were nausea (34%), vomiting (24%), fatigue (21%), and aspartate aminotransferase increased (17%). There were no dose limiting toxicities and enrollment continues. PK analysis showed dose proportional increases in Cmax and AUC. Amongst 21 efficacy evaluable pts, PRs were observed in 5 pts: 1 small cell lung and 1 breast with confirmed PR (cPR), both ongoing; 1 colorectal with unconfirmed PR (uPR), and 2 prostate with uPR and ongoing. In the 3 highest dose cohorts (total daily dose 2000 to 3000 mg), there were 3 PRs (2 uPR, 1cPR) and 7 SD out of 10 efficacy evaluable pts (all ongoing). Observations of decreasing p53 Y220C circulating tumor DNA and decreasing numbers of circulating tumor cells in pts further support on-target anti-tumor activity of PC14586. Conclusions: Enrollment to a Phase 1 study is feasible in a TP53 mutation selective population. PC14586 is safe and tolerated up to 3000 mg daily. Preliminary efficacy was achieved in heavily pretreated pts. Additional safety, PK, PD and efficacy data will be reported at the annual meeting. Clinical trial information: NCT04585750.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 Y220C prostate cancer predicted - sensitive PC14586 Case Reports/Case Series Actionable In a Phase I trial, PC14586 treatment resulted in unconfirmed partial responses in two patients with prostate cancer harboring TP53 Y220C (J Clin Oncol 40, no. 16_suppl (June 01, 2022) 3003); NCT04585750). detail...
TP53 Y220C Advanced Solid Tumor predicted - sensitive PC14586 Phase I Actionable In a Phase I trial, PC14586 treatment demonstrated safety and preliminary efficacy in patients with advanced solid tumors harboring TP53 Y220C, and resulted in 5 partial responses amongst 21 evaluable patients including confirmed partial responses in one small cell lung cancer and one breast cancer patient, and unconfirmed partial responses in one colorectal cancer and two prostate cancer patients (J Clin Oncol 40, no. 16_suppl (June 01, 2022) 3003); NCT04585750). detail...
TP53 Y220C breast cancer predicted - sensitive PC14586 Case Reports/Case Series Actionable In a Phase I trial, PC14586 treatment resulted in a partial response in a patient with breast cancer harboring TP53 Y220C (J Clin Oncol 40, no. 16_suppl (June 01, 2022) 3003); NCT04585750). detail...
TP53 Y220C colorectal cancer predicted - sensitive PC14586 Case Reports/Case Series Actionable In a Phase I trial, PC14586 treatment resulted in an unconfirmed partial response in a patient with colorectal cancer harboring TP53 Y220C (J Clin Oncol 40,no. 16_suppl (June 01, 2022) 3003); NCT04585750). detail...
TP53 Y220C lung small cell carcinoma predicted - sensitive PC14586 Case Reports/Case Series Actionable In a Phase I trial, PC14586 treatment resulted in a partial response in a patient with small cell lung cancer harboring TP53 Y220C (J Clin Oncol 40, no. 16_suppl (June 01, 2022) 3003); NCT04585750). detail...