학술논문
Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas
Document Type
article
Author
Wu, Jing; Yuan, Ying; Priel, Debra A Long; Fink, Danielle; Peer, Cody J; Sissung, Tristan M; Su, Yu-Ting; Pang, Ying; Yu, Guangyang; Butler, Madison K; Mendoza, Tito R; Vera, Elizabeth; Ahmad, Salman; Bryla, Christine; Lindsley, Matthew; Grajkowska, Ewa; Mentges, Kelly; Boris, Lisa; Antony, Ramya; Garren, Nancy; Siegel, Christine; Lollo, Nicole; Cordova, Christine; Aboud, Orwa; Theeler, Brett J; Burton, Eric M; Penas-Prado, Marta; Leeper, Heather; Gonzales, Javier; Armstrong, Terri S; Calvo, Katherine R; Figg, William D; Kuhns, Douglas B; Gallin, John I; Gilbert, Mark R
Source
Clinical Cancer Research. 27(12)
Subject
Language
Abstract
PurposeTo investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma.Patients and methodsThis two-stage phase I trial determined the MTD of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden.ResultsFifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12-24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value.ConclusionsZotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclib-induced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.