Title

Phase 0 Trial of AZD1775 in First-Recurrence Glioblastoma Patients

Document Type

Article

Abstract

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. 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. 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 G arrest, intensified double-strand DNA breakage, and programmed cell death. No drug-related adverse events were associated with this study. 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. .

Medical Subject Headings

Adult; Aged; Aged, 80 and over; Apoptosis (drug effects); Blood-Brain Barrier (drug effects); Cell Proliferation (drug effects); Female; Glioblastoma (blood, drug therapy, pathology); Humans; Male; Middle Aged; Neoplasm Recurrence, Local (blood, drug therapy, pathology); Protein Kinase Inhibitors (administration & dosage, pharmacokinetics); Pyrazoles (administration & dosage, pharmacokinetics); Pyrimidinones (administration & dosage, pharmacokinetics)

Publication Date

8-15-2018

Publication Title

Clinical cancer research : an official journal of the American Association for Cancer Research

E-ISSN

1557-3265

Volume

24

Issue

16

First Page

3820

Last Page

3828

PubMed ID

29798906

Digital Object Identifier (DOI)

10.1158/1078-0432.CCR-17-3348

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