Phase I study of single-agent AZD1775 (MK-1775), a wee1 kinase inhibitor, in patients with refractory solid tumors

Khanh Do, Deborah Wilsker, Jiuping Ji, Jennifer Zlott, Tomoko Freshwater, Robert J. Kinders, Jerry Collins, Alice P. Chen, James H. Doroshow, Shivaani Kummar

Research output: Contribution to journalArticlepeer-review

177 Scopus citations

Abstract

Purpose: Wee1 tyrosine kinase phosphorylates and inactivates cyclin-dependent kinase (Cdk) 1/2 in response to DNA damage. AZD1775 is a first-in-class inhibitor of Wee1 kinase with single-agent antitumor activity in preclinical models. We conducted a phase I study of single-agent AZD1775 in adult patients with refractory solid tumors to determine its maximum-tolerated dose (MTD), pharmacokinetics, and modulation of phosphorylated Tyr15-Cdk (pY15-Cdk) and phosphorylated histone H2AX (γH2AX) levels in paired tumor biopsies. Patients and Methods: AZD1775 was administered orally twice per day over 2.5 days per week for up to 2 weeks per 21-day cycle (3+3 design). At the MTD, paired tumor biopsies were obtained at baseline and after the fifth dose to determine pY15-Cdk and γH2AX levels. Six patients with BRCA-mutant solid tumors were also enrolled at the MTD Results: Twenty-five patients were enrolled. The MTD was established as 225 mg twice per day orally over 2.5 days per week for 2 weeks per 21-day cycle. Confirmed partial responses were observed in two patients carrying BRCA mutations: one with head and neck cancer and one with ovarian cancer. Common toxicities were myelosuppression and diarrhea. Dose-limiting toxicities were supraventricular tachyarrhythmia and myelosuppression. Accumulation of drug (t1/2 approximately 11 hours) was observed. Reduction in pY15-Cdk levels (two of five paired biopsies) and increases in γH2AX levels (three of five paired biopsies) were demonstrated Conclusion: This is the first report of AZD1775 single-agent activity in patients carrying BRCA mutations. Proof-of-mechanism was demonstrated by target modulation and DNA damage response in paired tumor biopsies.

Original languageEnglish (US)
Pages (from-to)3409-3415
Number of pages7
JournalJournal of Clinical Oncology
Volume33
Issue number30
DOIs
StatePublished - Oct 20 2015
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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