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Supplementary Methods and Figure Legends 1-2 from Characterization of an Akt Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

Supplementary Figure 2 from Characterization of an Akt Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

Supplementary Figure 1 from Characterization of an Akt Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

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.

Mutations in the TP53 gene are the most frequent somatic alterations in human cancer; approximately 50% of all human cancers possess mutations in TP53. Missense mutations in TP53 which result in a non-functional protein are the most frequently identified, these occur across the gene, however most hotspot mutations are localized within the DNA binding domain of the protein. Y220C is one such hotspot mutation, prevalent in ~1.8% of TP53 mutant tumors. PC14586 was structurally designed to bind tightly to a crevice within the mutant protein (KD~2.5 nM). It is the first orally bioavailable small molecule and selective reactivator of Y220C mutant p53 protein in clinical development. In Y220C mutant human cell lines, PC14586 was shown to stabilize the Y220C mutant in the wild type conformation, resulting in reactivation of p53 transcriptional activity and subsequent expression of its target proteins (e.g. p21, MDM2, Bax, PUMA). The reactivation of p53 function is highly selective to Y220C mutant cells and results in arrest of the cell cycle in vitro (IC50 ~0.230-1.8 μM). PC14586 has favorable pharmaceutical properties in pre-clinical species. In nude mice bearing Y220C mutant NUGC3 gastric cancer xenograft tumors, oral administration of PC14586 results in a dose responsive anti-tumor effect, with a target efficacious dose of 100 mg/kg daily resulting in approximately 80% tumor regression after 3 weeks. This anti-tumor effect was driven by a dose responsive pharmacodynamic modulation of the mutant p53 target. In human xenografts, PC14586 was shown to convert Y220C mutant to the wildtype conformation, resulting in activation of p53 transcription. This was demonstrated by the measurement of a p53 mRNA transcriptional signature and at the protein level by increases in p21 and MDM2 in the tumor and Macrophage Inhibitory Cytokine-1 (MIC-1) in both the tumor and plasma. In a C57Bl/6J syngeneic xenograft model bearing the Y220C mutation, administration of PC14586 at 100 mg/kg orally resulted in complete tumor cure in 80% of mice. PC14586 is well tolerated by pre-clinical species and possesses a favorable development profile. The safety and efficacy of PC14586 is currently being evaluated in a seamless Phase I/II clinical study that is a biomarker driven, solid tumor agnostic trial with patients whose tumor bears the Y220C TP53 mutation (NCT study identifier NCT04585750). Citation Format: Melissa Dumble, Lizhong Xu, Romyr Dominique, Binbin Liu, Hong Yang, Mary-Kate McBrayer, Dafydd Thomas, Bruce Fahr, Hongju Li, Kuo-Sen Huang, Kimberly Robell, Chris Mulligan, Brandon Russo, Anna Puzio-Kuter, Thomas Davis, Binh Vu. PC14586: The first orally bioavailable small molecule reactivator of Y220C mutant p53 in clinical development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB006.