Abstract C164: A phase 1 dose-escalation study of PRT2527, a cyclin-dependent kinase 9 (CDK9) inhibitor, in adult patients with advanced solid tumors: An updated analysis
Authors: Patel Manish R. , Basu-Mallick Astrayee , Dela Cruz Filemon , Orr Douglas , Spira Alex , Sonpavde Guru P. , Ghatalia Pooja , Lihou Christine , Sharma Neelesh , Scherle Peggy , Sun William , Sahasranaman Sri , Henry Jason T. 
Published: December 2023

Abstract
Introduction: CDK9 has emerged as a key dependency due to its role in regulation of transcription elongation in many “transcription-addicted” cancers. We report updated phase 1 results from an ongoing, open-label, multicenter, dose-escalation study of PRT2527 (NCT05159518), an investigational, potent, and highly selective CDK9 inhibitor being evaluated in patients (pts) with advanced solid tumors.
Methods: Enrolled adult pts had selected sarcomas, castration-resistant prostate cancer (CRPC), HR+/HER2– breast cancer (BC), non-small cell lung cancer (NSCLC), or MYC-amplified solid tumors that were relapsed or refractory to prior systemic treatment. Pts received intravenous PRT2527 (3, 6, 12, 15, or 18 mg/m2) once weekly (QW; 21-day cycle) using a Bayesian optimal interval design (n=3-6 per dose level); prophylactic anti-emetic and growth factor support was not required. Primary objectives were to evaluate dose-limiting toxicities (DLTs) and establish the maximum tolerated dose and recommended phase 2 dose of PRT2527. Secondary objectives were safety/tolerability, pharmacokinetics, and antitumor activity.
Results: At data cutoff (May 18, 2023), 29 pts with CRPC (38%), BC (17%), sarcoma (31%), pancreatic cancer (7%), and NSCLC (3%) were treated across 5 dose levels; 5 and 9 pts received 15 mg/m2 QW in dose escalation and confirmation, respectively. Seven pts had MYC amplification. Four pts were ongoing; 1 pt with chondrosarcoma received treatment for &gt;55 weeks. Two DLTs of grade 4 neutropenia were observed during dose escalation in the 15 and 18 mg/m2 QW cohorts. Overall, 100% of pts experienced all-cause, any-grade adverse events (AEs); the most frequent (≥15%) were nausea (45%), vomiting (38%), neutropenia (35%), fatigue (24%), and diarrhea (21%). Grade ≥3 all-cause and treatment-related AEs were reported in 48% and 21% of pts, respectively. Treatment-related grade ≥3 AEs were neutropenia (17%), anemia, leukopenia, thrombocytopenia, nausea, and pneumonia staphylococcal (3% each). Two deaths were reported while on study (sepsis and unknown cause; a third death occurred 38 days after the end of treatment); all were deemed unrelated to treatment. Four pts had dose reductions due to treatment-related AEs. Two pts required growth factor support for neutropenia. Eight (28%) pts had a best response of stable disease. Dose-dependent inhibition of CDK9 transcriptional targets was observed in all cohorts. A mean decrease of 76% (standard deviation [SD], 13%, n=8) in MCL1 and 77% (SD, 11%, n=8) in MYC mRNA was achieved 2 hours post infusion of the 15 mg/m2 QW dose; by 4 hours, MYC mRNA levels had rebounded to baseline levels (n=9) while MCL1 levels remained suppressed with a 60% (SD, 25%; n=9) inhibition.
Conclusions: In adults with solid tumors, PRT2527 demonstrated favorable tolerability, with manageable neutropenia and gastrointestinal events. Doses of 12 and 15 mg/m2 QW showed optimal target inhibition as predicted by the preclinical model. PRT2527 will be investigated as a combination therapy and in hematological malignancies.
Citation Format: Manish R. Patel MD, Astrayee Basu-Mallick MD, Filemon Dela Cruz MD, Douglas Orr MD, Alex Spira MD, PhD, Guru P. Sonpavde MD, Pooja Ghatalia MD, Christine Lihou BSc, Neelesh Sharma MD, PhD, Peggy Scherle PhD, William Sun PhD, Sri Sahasranaman, Jason T. Henry MD. A phase 1 dose-escalation study of PRT2527, a cyclin-dependent kinase 9 (CDK9) inhibitor, in adult patients with advanced solid tumors: An updated analysis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C164.