Abstract CT173: A phase 1, open-label, multicenter, dose-escalation study of PRT2527, a cyclin-dependent kinase 9 (CDK9) inhibitor, in adult patients (pts) with advanced solid tumors
Authors: Henry Jason T. , Orr Douglas , Basu-Mallick Atrayee , Spira Alex , Lihou Christine , Sharma Neelesh , Scherle Peggy , Chiaverelli Rachel , Patel Manish R. 
Published: April 2023

Abstract
Background: CDK9 is a key regulator of transcription elongation and recent studies suggest selective CDK9 inhibition may be a promising approach to treat “transcription-addicted” cancers that are dependent on oncogenic drivers with a short half-life. We report phase 1 dose-escalation results from an ongoing open-label study of PRT2527 (NCT05159518), a potent and highly selective CDK9 inhibitor, in pts with advanced solid tumors.
Methods: Key inclusion criteria include pts aged ≥18 years; selected sarcomas, castrate-resistant prostate cancer (CRPC), HR+/HER2- breast cancer, non-small cell lung cancer, or MYC-amplified solid tumors; received prior therapy; measurable disease (evaluable for CRPC); ECOG PS ≤1; and adequate organ function. Central nervous system disease is allowed if stable and adequately controlled. Pts received a once-weekly (QW; 21-day cycle) infusion of PRT2527 (3, 6, and 12 mg/m2 QW, n=3 pts per dose level using a Bayesian optimal interval dose escalation design) until intolerance, progression, death, or withdrawal. Primary objectives were to evaluate dose-limiting toxicities (DLT), establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of PRT2527. Secondary objectives included safety and tolerability, pharmacokinetics, and antitumor activity.
Results: At data cutoff (30 September 2022), 9 pts (CRPC, n=5; breast cancer, n=2; sarcoma, n=2) were treated in the first 3 dose levels of dose escalation. Median age was 64 (range, 57-73) years and 56% of pts were male. No DLTs were observed, the MTD was not reached, and evaluation of the RP2D is ongoing. Overall, 89% of pts have discontinued therapy (75% due to progressive disease); no discontinuations or dose reductions due to adverse events (AEs) and no deaths were reported. One pt on 12 mg/m2 QW had a dose interruption due to grade 2 myalgia and arthralgia; both events were considered related to study drug. All-cause, any grade AEs occurred in 89% of pts, most commonly nausea (44%), decreased appetite (33%), diarrhea (33%), and vomiting (33%). All-cause grade 3/4 AEs occurred in 22% of pts, including anemia (11%) and hyperglycemia (11%); both were unrelated to study treatment. One serious AE unrelated to treatment was reported (pneumothorax). Dose-dependent inhibition of CDK9 transcriptional targets was observed. A mean decrease of 88% (SD, 2.4%; n=3) in MCL1 and MYC mRNA was achieved 2 hours post-infusion of the 12 mg/m2 dose; by 4 hours post-infusion, expression levels had rebounded to 50% (SD, 2.7%; n=3; MYC) and 78% (SD, 6.4%; n=3; MCL1) inhibition.
Conclusions: PRT2527 is generally well tolerated in adults with advanced solid tumors. Updated data (including efficacy) will be presented.
Citation Format: Jason T. Henry, Douglas Orr, Atrayee Basu-Mallick, Alex Spira, Christine Lihou, Neelesh Sharma, Peggy Scherle, Rachel Chiaverelli, Manish R. Patel. A phase 1, open-label, multicenter, dose-escalation study of PRT2527, a cyclin-dependent kinase 9 (CDK9) inhibitor, in adult patients (pts) with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT173.