title: Phase I Study of Single-Agent AZD1775 (MK-1775), a Wee1 Kinase Inhibitor, in Patients With Refractory Solid Tumors.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Khanh Do, Jennifer Zlott, Jerry Collins, Alice P. Chen, James H. Doroshow, and Shivaani Kummar, National Cancer Institute, Bethesda, MD; Deborah Wilsker, Jiuping Ji, and Robert J. Kinders, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD; and Tomoko Freshwater, Merck Research Laboratories-Oncology, Boston, MA.
authors.forename: Khanh
authors.initials: K
authors.lastname: Do
authors.affiliation: Khanh Do, Jennifer Zlott, Jerry Collins, Alice P. Chen, James H. Doroshow, and Shivaani Kummar, National Cancer Institute, Bethesda, MD; Deborah Wilsker, Jiuping Ji, and Robert J. Kinders, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD; and Tomoko Freshwater, Merck Research Laboratories-Oncology, Boston, MA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Wilsker
authors.affiliation: Khanh Do, Jennifer Zlott, Jerry Collins, Alice P. Chen, James H. Doroshow, and Shivaani Kummar, National Cancer Institute, Bethesda, MD; Deborah Wilsker, Jiuping Ji, and Robert J. Kinders, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD; and Tomoko Freshwater, Merck Research Laboratories-Oncology, Boston, MA.
authors.forename: Jiuping
authors.initials: J
authors.lastname: Ji
authors.affiliation: Khanh Do, Jennifer Zlott, Jerry Collins, Alice P. Chen, James H. Doroshow, and Shivaani Kummar, National Cancer Institute, Bethesda, MD; Deborah Wilsker, Jiuping Ji, and Robert J. Kinders, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD; and Tomoko Freshwater, Merck Research Laboratories-Oncology, Boston, MA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Zlott
authors.affiliation: Khanh Do, Jennifer Zlott, Jerry Collins, Alice P. Chen, James H. Doroshow, and Shivaani Kummar, National Cancer Institute, Bethesda, MD; Deborah Wilsker, Jiuping Ji, and Robert J. Kinders, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD; and Tomoko Freshwater, Merck Research Laboratories-Oncology, Boston, MA.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Freshwater
authors.affiliation: Khanh Do, Jennifer Zlott, Jerry Collins, Alice P. Chen, James H. Doroshow, and Shivaani Kummar, National Cancer Institute, Bethesda, MD; Deborah Wilsker, Jiuping Ji, and Robert J. Kinders, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD; and Tomoko Freshwater, Merck Research Laboratories-Oncology, Boston, MA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kinders
authors.affiliation: Khanh Do, Jennifer Zlott, Jerry Collins, Alice P. Chen, James H. Doroshow, and Shivaani Kummar, National Cancer Institute, Bethesda, MD; Deborah Wilsker, Jiuping Ji, and Robert J. Kinders, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD; and Tomoko Freshwater, Merck Research Laboratories-Oncology, Boston, MA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Collins
authors.affiliation: Khanh Do, Jennifer Zlott, Jerry Collins, Alice P. Chen, James H. Doroshow, and Shivaani Kummar, National Cancer Institute, Bethesda, MD; Deborah Wilsker, Jiuping Ji, and Robert J. Kinders, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD; and Tomoko Freshwater, Merck Research Laboratories-Oncology, Boston, MA.
authors.forename: Alice P
authors.initials: AP
authors.lastname: Chen
authors.affiliation: Khanh Do, Jennifer Zlott, Jerry Collins, Alice P. Chen, James H. Doroshow, and Shivaani Kummar, National Cancer Institute, Bethesda, MD; Deborah Wilsker, Jiuping Ji, and Robert J. Kinders, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD; and Tomoko Freshwater, Merck Research Laboratories-Oncology, Boston, MA.
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.affiliation: Khanh Do, Jennifer Zlott, Jerry Collins, Alice P. Chen, James H. Doroshow, and Shivaani Kummar, National Cancer Institute, Bethesda, MD; Deborah Wilsker, Jiuping Ji, and Robert J. Kinders, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD; and Tomoko Freshwater, Merck Research Laboratories-Oncology, Boston, MA. kummars@mail.nih.gov.
authors.forename: Shivaani
authors.initials: S
authors.lastname: Kummar
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D011744:Pyrimidinones; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C549567:adavosertib