Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas

Abstract

To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide (TMZ) in patients with recurrent high-grade astrocytoma.Experimental Design: This two-stage phase 1 trial determined the maximum tolerated dose (MTD) of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) TMZ using a Bayesian Optimal Interval design; then a randomized cohortexpansion compared the progression-free survival rate at 4 month (PFS4) of the two arms for an efficient determination of a TMZ schedule to combine with zotiraciclib at MTD. Pharmacokinetics (PK) and pharmacogenomic (PG) 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 250mg in both arms and thus selected for the cohort expansion. Dose-dense TMZ plus zotiraciclib (PSF4 40%) compared favorably with metronomic TMZ (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. PK/PG analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUC inf value.Conclusions: Zotiraciclib combined with TMZ is safe in patients with recurrent highgrade 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.

Targeting CDK9 for the Treatment of Glioblastoma

“…The combined treatment also suppressed phosphorylation of RNA Pol II and reduced protein expression of CDK9 to a greater extent than zotiraciclib did alone, though how IFN-β mediates this synergistic effect remains to be explored [ 68 ]. On a separate but related note, a pharmacokinetic study of zotiraciclib, conducted as part of a phase I trial for patients with recurrent anaplastic astrocytoma and glioblastoma (NCT02942264) (see Section 5.2 ), revealed a significant increase in patient plasma concentrations of cytokines, including IP-10, at 24 h after an oral dose of zotiraciclib [ 69 ]. IP-10 has been reported to promote an anti-tumor immune response by attracting cytotoxic T and NK cells [ 10 ], though whether this occurs following zotiraciclib treatment remains to be determined.…”

“…While it primarily targets CDK9 (with an IC 50 value of 3 nM) [ 78 ], it also inhibits CDKs 1, 2, and 7, Janus Kinase 2 (JAK2), and FLT3 [ 26 ]. Dose-limiting toxicities of zotiraciclib in a phase I trial for patients with recurrent anaplastic astrocytoma and glioblastoma included neutropenia as well, but the drug demonstrated an overall tolerable toxicity profile (see Section 5.3 ) and was granted orphan drug designation by the FDA in 2019 for treatment of gliomas [ 69 ].…”

“…Based on the synergistic effects of zotiraciclib and TMZ demonstrated in the preclinical studies, a phase I/II clinical trial of zotiraciclib plus dose-dense or metronomic TMZ in patients with recurrent glioblastoma and anaplastic astrocytoma (AA) (NCT02942264) was launched [ 88 ], and the phase I part has recently been completed [ 69 ]. In this two-stage phase I study, the maximum tolerated dose (MTD) of zotiraciclib combined with either dose-dense TMZ (125 mg/m 2 × 7 days on/7 days off) or metronomic TMZ (50 mg/m 2 daily) was first determined [ 69 ]. This was followed by a randomized cohort expansion to compare the progression-free survival rate at 4 months (PSF4) between the two arms to determine a TMZ schedule to combine with zotiraciclib at the MTD [ 69 ].…”

“…In this two-stage phase I study, the maximum tolerated dose (MTD) of zotiraciclib combined with either dose-dense TMZ (125 mg/m 2 × 7 days on/7 days off) or metronomic TMZ (50 mg/m 2 daily) was first determined [ 69 ]. This was followed by a randomized cohort expansion to compare the progression-free survival rate at 4 months (PSF4) between the two arms to determine a TMZ schedule to combine with zotiraciclib at the MTD [ 69 ]. The MTD of zotiraciclib in both arms was found to be 250 mg, and dose-dense TMZ was selected based on a favorable PFS4 of 40% compared to metronomic TMZ (25%) [ 69 ].…”

“…This was followed by a randomized cohort expansion to compare the progression-free survival rate at 4 months (PSF4) between the two arms to determine a TMZ schedule to combine with zotiraciclib at the MTD [ 69 ]. The MTD of zotiraciclib in both arms was found to be 250 mg, and dose-dense TMZ was selected based on a favorable PFS4 of 40% compared to metronomic TMZ (25%) [ 69 ]. Zotiraciclib was found to be safe and tolerable, though patients experienced some side effects (see Section 5.3 ).…”