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Takebe N, Naqash AR, O'Sullivan Coyne G, et al. Safety, Antitumor Activity, and Biomarker Analysis in a Phase I Trial of the Once-daily Wee1 Inhibitor Adavosertib (AZD1775) in Patients with Advanced Solid Tumors. Clin Cancer Res. 2021;27(14):3834-3844doi: 10.1158/1078-0432.CCR-21-0329.
Takebe, N., Naqash, A. R., O'Sullivan Coyne, G., Kummar, S., Do, K., Bruns, A., Juwara, L., Zlott, J., Rubinstein, L., Piekarz, R., Sharon, E., Streicher, H., Mittra, A., Miller, S. B., Ji, J., Wilsker, D., Kinders, R. J., Parchment, R. E., Chen, L., Chang, T. C., Das, B., Mugundu, G., Doroshow, J. H., & Chen, A. P. (2021). Safety, Antitumor Activity, and Biomarker Analysis in a Phase I Trial of the Once-daily Wee1 Inhibitor Adavosertib (AZD1775) in Patients with Advanced Solid Tumors. Clinical cancer research : an official journal of the American Association for Cancer Research, 27(14), 3834-3844. https://doi.org/10.1158/1078-0432.CCR-21-0329
Takebe, Naoko, et al. "Safety, Antitumor Activity, and Biomarker Analysis in a Phase I Trial of the Once-daily Wee1 Inhibitor Adavosertib (AZD1775) in Patients with Advanced Solid Tumors." Clinical cancer research : an official journal of the American Association for Cancer Research vol. 27,14 (2021): 3834-3844. doi: https://doi.org/10.1158/1078-0432.CCR-21-0329
Takebe N, Naqash AR, O'Sullivan Coyne G, Kummar S, Do K, Bruns A, Juwara L, Zlott J, Rubinstein L, Piekarz R, Sharon E, Streicher H, Mittra A, Miller SB, Ji J, Wilsker D, Kinders RJ, Parchment RE, Chen L, Chang TC, Das B, Mugundu G, Doroshow JH, Chen AP. Safety, Antitumor Activity, and Biomarker Analysis in a Phase I Trial of the Once-daily Wee1 Inhibitor Adavosertib (AZD1775) in Patients with Advanced Solid Tumors. Clin Cancer Res. 2021 Jul 15;27(14):3834-3844. doi: 10.1158/1078-0432.CCR-21-0329. Epub 2021 Apr 16. PMID: 33863809; PMCID: PMC8282703.
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Clin Cancer Res. 2021 Jul 15;27(14):3834-3844. doi: 10.1158/1078-0432.CCR-21-0329. Epub 2021 Apr 16.

Safety, Antitumor Activity, and Biomarker Analysis in a Phase I Trial of the Once-daily Wee1 Inhibitor Adavosertib (AZD1775) in Patients with Advanced Solid Tumors.

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

Naoko Takebe, Abdul Rafeh Naqash, Geraldine O'Sullivan Coyne, Shivaani Kummar, Khanh Do, Ashley Bruns, Lamin Juwara, Jennifer Zlott, Larry Rubinstein, Richard Piekarz, Elad Sharon, Howard Streicher, Arjun Mittra, Sarah B Miller, Jiuping Ji, Deborah Wilsker, Robert J Kinders, Ralph E Parchment, Li Chen, Ting-Chia Chang, Biswajit Das, Ganesh Mugundu, James H Doroshow, Alice P Chen

Affiliations

  1. Division of Cancer Treatment and Diagnosis, NCI, Bethesda, Maryland.
  2. Center for Cancer Research, NCI, Bethesda, Maryland.
  3. Clinical Monitoring Research Program, Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
  4. Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
  5. Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
  6. AstraZeneca, Clinical Pharmacology, Waltham, Massachusetts.
  7. Division of Cancer Treatment and Diagnosis, NCI, Bethesda, Maryland. [email protected].

PMID: 33863809 PMCID: PMC8282703 DOI: 10.1158/1078-0432.CCR-21-0329

Abstract

PURPOSE: The Wee1 kinase inhibitor adavosertib abrogates cell-cycle arrest, leading to cell death. Prior testing of twice-daily adavosertib in patients with advanced solid tumors determined the recommended phase II dose (RPh2D). Here, we report results for once-daily adavosertib.

PATIENTS AND METHODS: A 3 + 3 dose-escalation design was used, with adavosertib given once daily on days 1 to 5 and 8 to 12 in 21-day cycles. Molecular biomarkers of Wee1 activity, including tyrosine 15-phosphorylated Cdk1/2 (pY15-Cdk), were assessed in paired tumor biopsies. Whole-exome sequencing and RNA sequencing of remaining tumor tissue identified potential predictive biomarkers.

RESULTS: Among the 42 patients enrolled, the most common toxicities were gastrointestinal and hematologic; dose-limiting toxicities were grade 4 hematologic toxicity and grade 3 fatigue. The once-daily RPh2D was 300 mg. Six patients (14%) had confirmed partial responses: four ovarian, two endometrial. Adavosertib plasma exposures were similar to those from twice-daily dosing. On cycle 1 day 8 (pre-dose), tumor pY15-Cdk levels were higher than baseline in four of eight patients, suggesting target rebound during the day 5 to 8 dosing break. One patient who progressed rapidly had a tumor

CONCLUSIONS: We determined the once-daily adavosertib RPh2D and observed activity in patients with ovarian or endometrial carcinoma, including two with baseline

©2021 American Association for Cancer Research.

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