Abstract A019: Phase 1, first-in-human, dose-expansion study of oral TP-1287, a cyclin dependent kinase 9 (CDK9) inhibitor, in patients with sarcoma
Authors: Wagner Andrew J. , Cote Gregory M. , Richards Donald , Vogelzang Nicholas J. , Edenfield William J. , Gross Mitchell E. , Mar Lynn , Fine Gil D. , Dow Edward , Charlson John A. 
Published: September 2022

Abstract
Background: CDK9 blockade inhibits tumor growth and progression by impairing the transcription of key oncogenes, such as MCL1 and MYC. TP-1287 is an orally delivered phosphate prodrug of the CDK9 inhibitor alvocidib. The anti-tumor activity of alvocidib has previously been shown in vitro in a Ewing sarcoma cell line and in vivo in a mouse Ewing sarcoma xenograft model. TP-1287 is being investigated in a phase 1 dose escalation and dose expansion study in patients with solid tumors (escalation) and sarcoma (expansion) (NCT03604783). The design of the expansion part of the phase 1 study in patients with sarcoma is herein described. Methods: Thirty patients with sarcoma will be enrolled. Key eligibility criteria are age ≥18 years (≥16 years if ≥40 kg); histologically confirmed locally advanced or metastatic unresectable Ewing sarcoma, dedifferentiated liposarcoma, or synovial sarcoma (10 patients each); 1–3 prior lines of therapy (including an anthracycline); Eastern Cooperative Oncology Group performance status of ≤1; acceptable liver and renal function, and acceptable hematologic and coagulation status. Exclusion criteria include a history of certain cardiovascular diseases (including heart failure and myocardial infarction [≤6 months]); seizure disorder requiring anticonvulsant therapy; presence of symptomatic central nervous system metastatic disease or disease that requires local therapy ≤2 weeks; severe chronic obstructive pulmonary disease with hypoxemia; active infections; or treatment with surgery, chemotherapy, or investigational therapy within 28 days or 5 half-lives (whichever occurs first). Patients will be treated at the recommended phase 2 dose established during dose escalation (11 mg twice daily orally, continuous dosing) and will continue to receive treatment with the same dose/schedule if they successfully complete a 28-day treatment cycle without significant treatment-related toxicity or progressive disease. Assessments will be performed on Day 1 and Day 15 of each cycle. Assessments for response and tumor burden will be done after Cycle 2 and at the end of every other cycle thereafter. The primary objective is objective response rate; secondary objectives are progression-free survival at 16 and 24 weeks and safety; and exploratory objectives are systemic exposure, antitumor activity (by objective radiographic assessment), and pharmacodynamics. Tumor tissue concentrations may be measured in patients who consent to optional tumor biopsies. Statistical analysis for all safety and efficacy parameters will be primarily descriptive in nature; time-to-event variables will be summarized via Kaplan-Meier. The dose expansion cohort is currently recruiting in the United States. Results: N/A. Conclusions: N/A.
Citation Format: Andrew J. Wagner, Gregory M. Cote, Donald Richards, Nicholas J. Vogelzang, William J. Edenfield, Mitchell E. Gross, Lynn Mar, Gil D. Fine, Edward Dow, John A. Charlson. Phase 1, first-in-human, dose-expansion study of oral TP-1287, a cyclin dependent kinase 9 (CDK9) inhibitor, in patients with sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A019.