Ben George, MD from Froedtert & Medical College discusses an ASCO 2020 abstract entitied A phase I, first-in-human, open-label, dose‑escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP‑1287 administered daily to patients with advanced solid tumors
Context:
TP-1287 is an alvocidib, cyclin-dependent kinase 9 (CDK9) inhibitor, orally bioavailable phosphate prodrug. TP-1287 demonstrates powerful inhibition of CDK9 and intracellular kinases. Inhibition of CDK9 contributes to downregulation of the BCL-2 family member, MCL-1, which in turn inhibits tumor development of prostate , breast, and lung carcinomas in preclinical animal models.
Approaches:
This is a Phase 1 multicenter dose escalation study in patients with advanced solid tumors using a conventional 3 + 3 template with a changed Fibonacci scheme to investigate the protection and clinical activity of TP-1287. To assess TP-1287 as a single agent in patients with castrate-resistant prostate cancer, patients will be added to the maximum tolerated dose (i.e. the expansion cohort).
Reviews:
A spectrum of doses from 1 mg QD to 11 mg BID over 7 cohorts was obtained by 22 patients who were enrolled between December 2018 and January 2020. As of the data cut-off date, data is available for 20 patients. In near linear fashion, TP-1287 plasma PK Cmax and AUC increased over cohorts 1 through 6, reaching 80 ng / mL and 499.3 ng*h / mL in cohort 6 for Cmax and AUC. Treatment with TP-1287 resulted in dose-dependent phospho-RNA Pol II reduction, consistent with CDK9 inhibition, as assessed by a flow cytometric assay evaluating pharmacodynamic changes in PBMC phosphorylation status. Grade 3 AE was the most commonly found in 2 patients with unrelated anemia. All other Grade 3 (9 events/7 patients) and Grade 4 (1 new CNS meta event / seizure) events were unlikely to be related or unrelated. One sarcoma patient with PR (15+cycles), one RCC patient with SD (7+cycles), and two bladder cancer patients with SD (6 and 8 cycles) demonstrated clinical benefit.Â
Findings:
These results indicate that TP-1287 is tolerated as monotherapy in patients with selected indications with heavily pretreated, relapsed, refractory solid tumors and further clinical research is needed. Details on clinical trials: NCT03298984.