Phase 0 Trial of AZD1775 in First-Recurrence Glioblastoma Patients

Abstract

Purpose: AZD1775 is a first-in-class Wee1 inhibitor with dual function as a DNA damage sensitizer and cytotoxic agent. A phase I study of AZD1775 for solid tumors suggested activity against brain tumors, but a preclinical study indicated minimal blood-brain barrier penetration in mice. To resolve this controversy, we examined the pharmacokinetics and pharmacodynamics of AZD1775 in patients with first-recurrence, glioblastoma.Patients and Methods: Twenty adult patients received a single dose of AZD1775 prior to tumor resection and enrolled in either a dose-escalation arm or a time-escalation arm. Sparse pharmacokinetic blood samples were collected, and contrast-enhancing tumor samples were collected intraoperatively. AZD1775 total and unbound concentrations were determined by a validated LC/MS-MS method. Population pharmacokinetic analysis was performed to characterize AZD1775 plasma pharmacokinetic profiles. Pharmacodynamic endpoints were compared to matched archival tissue.Results: The AZD1775 plasma concentration-time profile following a single oral dose in patients with glioblastoma was well-described by a one-compartment model. Glomerular filtration rate was identified as a significant covariate on AZD1775 apparent clearance. AZD1775 showed good brain tumor penetration, with a median unbound tumor-to-plasma concentration ratio of 3.2, and achieved potential pharmacologically active tumor concentrations. Wee1 pathway suppression was inferred by abrogation of G₂ arrest, intensified double-strand DNA breakage, and programmed cell death. No drug-related adverse events were associated with this study.Conclusions: In contrast to recent preclinical data, our phase 0 study of AZD 1775 in recurrent glioblastoma indicates good human brain tumor penetration, provides the first evidence of clinical biological activity in human glioblastoma, and confirms the utility of phase 0 trials as part of an accelerated paradigm for drug development in patients with glioma. Clin Cancer Res; 24(16); 3820-8. ©2018 AACRSee related commentary by Vogelbaum, p. 3790.

Trial registration: ClinicalTrials.gov NCT02207010.

Figure 1.

Phase 0 study design composed of the dose-escalation arm (A) and the time-escalation arm (B–D).

Figure 2.

AZD1775 plasma and tumor pharmacokinetics in patients with glioblastoma receiving a single oral dose. A, AZD1775 total plasma concentration-time profiles. Symbols represent observed concentrations; solid, dash, and dot lines represent pharmacokinetic profiles fitted by the final population pharmacokinetic model. B, Unbound AZD1775 tumor concentrations. C, AZD1775 total tumor-to-plasma concentration ratios. D, AZD1775 unbound tumor-to-plasma concentration ratios. Symbols represent observed data; boxplot represents 25th, 50th (median), and 75th percentiles of the observed data.

Figure 3.

In matched archival tissues following drug exposure, Wee1 pathway suppression was inferred by intensified double-strand DNA breakage (A), abrogation of G₂-arrest (B), and programmed cell death (C). Horizontal line marks the mean fold change.

Figure 4.

In the time-escalation arm, γH2AX expression, phosphohistone-3 expression (PH3), and CC3 expression all demonstrated peak changes 8 hours following AZD1775 administration. Horizontal line marks the mean fold change.