1. Phase I Study of Single-Agent AZD1775 (MK-1775), a Wee1 Kinase Inhibitor, in Patients With Refractory Solid Tumors.
- Author
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Do K, Wilsker D, Ji J, Zlott J, Freshwater T, Kinders RJ, Collins J, Chen AP, Doroshow JH, and Kummar S
- Subjects
- Administration, Oral, Adult, Aged, Antineoplastic Agents adverse effects, Antineoplastic Agents blood, Antineoplastic Agents pharmacokinetics, Cell Cycle Proteins antagonists & inhibitors, Cell Cycle Proteins metabolism, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Male, Middle Aged, Neoplasms blood, Neoplasms enzymology, Neoplasms metabolism, Nuclear Proteins antagonists & inhibitors, Nuclear Proteins metabolism, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors blood, Protein Kinase Inhibitors pharmacokinetics, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases metabolism, Pyrazoles adverse effects, Pyrazoles blood, Pyrazoles pharmacokinetics, Pyrimidines adverse effects, Pyrimidines blood, Pyrimidines pharmacokinetics, Pyrimidinones, Young Adult, Antineoplastic Agents administration & dosage, Neoplasms drug therapy, Protein Kinase Inhibitors administration & dosage, Pyrazoles administration & dosage, Pyrimidines administration & dosage
- 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., (© 2015 by American Society of Clinical Oncology.)
- Published
- 2015
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