Phase i study of zotiraciclib in combination with temozolomide for patients with recurrent high-grade astrocytomas

Jing Wu*, Ying Yuan, Debra A.Long Priel, Danielle Fink, Cody J. Peer, Tristan M. Sissung, Yu Ting Su, Ying Pang, Guangyang Yu, Madison K. Butler, Tito R. Mendoza, Elizabeth Vera, Salman Ahmad, Christine Bryla, Matthew Lindsley, Ewa Grajkowska, Kelly Mentges, Lisa Boris, Ramya Antony, Nancy GarrenChristine Siegel, Nicole Lollo, Christine Cordova, Orwa Aboud, Brett J. Theeler, Eric M. Burton, Marta Penas-Prado, Heather Leeper, Javier Gonzales, Terri S. Armstrong, Katherine R. Calvo, William D. Figg, Douglas B. Kuhns, John I. Gallin, Mark R. Gilbert

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Purpose: To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma. Patients and Methods: This two-stage phase I trial determined theMTDof 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. Results: Fifty-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. Conclusions: Zotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclibinduced 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.

Original languageEnglish
Pages (from-to)3298-3306
Number of pages9
JournalClinical Cancer Research
Volume27
Issue number12
DOIs
StatePublished - Jun 2021
Externally publishedYes

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