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.

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 WEE1 mutation and potentially compensatory PKMYT1 overexpression. Baseline CCNE1 overexpression occurred in both of two responding patients, only one of whom had CCNE1 amplification, and in zero of three nonresponding patients.

CONCLUSIONS:

We determined the once-daily adavosertib RPh2D and observed activity in patients with ovarian or endometrial carcinoma, including two with baseline CCNE1 mRNA overexpression. Future studies will determine whether CCNE1 overexpression is a predictive biomarker for adavosertib.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 14 Pg. 3834-3844 (07 15 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 33863809 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• Cell Cycle Proteins
• Enzyme Inhibitors
• Pyrazoles
• Pyrimidinones
• Protein-Tyrosine Kinases
• WEE1 protein, human
• adavosertib

Topics

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor (analysis)
• Cell Cycle Proteins (antagonists & inhibitors)
• Drug Administration Schedule
• Enzyme Inhibitors (adverse effects, therapeutic use)
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (chemistry, drug therapy)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrazoles (adverse effects, therapeutic use)
• Pyrimidinones (adverse effects, therapeutic use)
• Treatment Outcome