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 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 AUC_inf 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.

Figure 1.

CONSORT Diagram

Figure 2.

Neutrophil and PK analysis. A Plot of the percentage of baseline absolute neutrophil count over time in each patient (n=13). B Serum concentration of zotiraciclib over time after treatment in each patient (n=13). C Neutrophil ROS production was measured by luminol-enhanced chemiluminescence (ECL), using fMLF, zymosan and phorbol myristate acetate (PMA) as stimuli. The area under the curve (AUC) was calculated as the measure of ROS production. Data are expressed as the mean ± SD. Black bar: daily normal neutrophil; blue bar: patient baseline; red bar: 24hr after treatment; green bar: 72hr after treatment. ns, not significant, ** p<0.01, *** p< 0.001. (C) Changes of fMLF (top panel), op-zymosan (middle panel), and PMA-induced ROS production at baseline (blue lines), 24 hours (red lines) and 72 hours (green lines) after treatment in a representative case compared to the normal neutrophils (black lines).

Figure 3.

Cytokine analysis in patients received an oral dose of zotiraciclib at 250mg. Cytokine level of a representative study subject versus time points from 0–72 hours after zotiraciclib dosing is plotted to demonstrate the temporal change of the cytokine release. The vertical dotted red line indicates the peak time of each cytokine release. The gray area represents the normal range defined as the mean ± 2 standard deviation that was generated from 114 healthy volunteer. The mean level of cytokines at baseline and peak time from entire cohort of patients are summarized in the insert in each plot (n=13). Cytokine level at peak time was compared with baseline level using paired t-test. n=13. * p<0.05, ** p<0.01, *** p<0.001.

Figure 4.

AUCinf of zotiraciclib in patients have homozygous loss (C/C, n=2), heterozygous (C/T n=6) and wild type (T/T, n=5) of CYP1A-5347>C, a variant is suspected to be loss of function of CYP1A2. p=0.044 by Jonckeere-Terpstra trend test.