- 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
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 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.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. 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.