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Updated: Apr 12, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Phase I Study of Single-Agent AZD1775 (MK-1775), a Wee1 Kinase Inhibitor, in Patients With Refractory Solid Tumors
Khanh Do1, Deborah Wilsker1, Jiuping Ji1
1Khanh 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.
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.
Insights
The Wee1 kinase inhibitor AZD1775 showed antitumor activity in patients with refractory solid tumors, particularly those with BRCA mutations. This study established the maximum tolerated dose and demonstrated target engagement via DNA damage response modulation.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Wee1 tyrosine kinase regulates cell cycle progression by inactivating cyclin-dependent kinase 1/2 (Cdk1/2) in response to DNA damage.
- AZD1775 is a novel, first-in-class Wee1 kinase inhibitor with demonstrated preclinical antitumor efficacy.
- Understanding the clinical activity and safety profile of AZD1775 is crucial for its therapeutic development.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD) of single-agent AZD1775 in adult patients with refractory solid tumors.
- To evaluate the pharmacokinetics of AZD1775.
- To assess target modulation by measuring phosphorylated Tyr15-Cdk (pY15-Cdk) and phosphorylated histone H2AX (γH2AX) levels in paired tumor biopsies.
Main Methods:
- A Phase I, 3+3 dose-escalation study was conducted.
- AZD1775 was administered orally twice daily for 2.5 days per week for 2 weeks in 21-day cycles.
- Paired tumor biopsies were collected at baseline and after dose 5 to assess pY15-Cdk and γH2AX levels. Six patients with BRCA-mutant tumors were enrolled at the MTD.
Main Results:
- The MTD was determined to be 225 mg twice daily.
- Two partial responses were observed in patients with BRCA mutations (head and neck cancer, ovarian cancer).
- Target modulation was confirmed with decreased pY15-Cdk (2/5) and increased γH2AX (3/5) in paired biopsies. Common toxicities included myelosuppression and diarrhea.
Conclusions:
- This study reports the first single-agent activity of AZD1775 in patients with BRCA mutations.
- Proof-of-mechanism was established through observed target modulation and induction of DNA damage response.
- AZD1775 demonstrates potential as a therapeutic agent, particularly in BRCA-mutated cancers.
