@article{f6ca6ef1e18e4559b66778866090b9f2,
title = "Phase i study of zotiraciclib in combination with temozolomide for patients with recurrent high-grade astrocytomas",
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.",
author = "Jing Wu and Ying Yuan and Priel, {Debra A.Long} and Danielle Fink and Peer, {Cody J.} and Sissung, {Tristan M.} and Su, {Yu Ting} and Ying Pang and Guangyang Yu and Butler, {Madison K.} and Mendoza, {Tito R.} and Elizabeth Vera and Salman Ahmad and Christine Bryla and Matthew Lindsley and Ewa Grajkowska and Kelly Mentges and Lisa Boris and Ramya Antony and Nancy Garren and Christine Siegel and Nicole Lollo and Christine Cordova and Orwa Aboud and Theeler, {Brett J.} and Burton, {Eric M.} and Marta Penas-Prado and Heather Leeper and Javier Gonzales and Armstrong, {Terri S.} and Calvo, {Katherine R.} and Figg, {William D.} and Kuhns, {Douglas B.} and Gallin, {John I.} and Gilbert, {Mark R.}",
note = "Funding Information: The authors thank NCI Intramural Research Program and NIH Lasker Clinical Research Scholars Program for the funding and support for the research in this article. We also thank Adastra Pharmaceuticals for providing the drug supply for clinical trial. Finally, our special thanks go to all patients and their families for their participation in the clinical trial and the support for our clinical research. Funding Information: The authors thank NCI Intramural Research Program and NIH Lasker Clinical Research Scholars Program for the funding and support for the research in this article. Wealso thank Adastra Pharmaceuticals for providing the drug supply for clinical trial. Finally, our special thanks go to all patients and their families for their participation in the clinical trial and the support for our clinical research. Funding from NIH Lasker Clinical Research Scholars Program and NCI Intramural Research Program was used toward the design, implementation of the clinical trial, data collection, analysis, and generating the article. This research project was supported in part from the NIH, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Adastra Pharmaceuticals provided the drug supply for clinical trial. All authors have the full access to the data used to generate the report and agreed with the findings. Funding Information: Funding from NIH Lasker Clinical Research Scholars Program and NCI Intramural Research Program was used toward the design, implementation of the clinical trial, data collection, analysis, and generating the article. This research project was supported in part from the NIH, under contract no. HHSN261200800001E. The Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",
year = "2021",
month = jun,
doi = "10.1158/1078-0432.CCR-20-4730",
language = "English",
volume = "27",
pages = "3298--3306",
journal = "Clinical Cancer Research",
issn = "1078-0432",
number = "12",
}