Phase I, dose-finding study of AZD8931, an inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling, in patients with advanced solid tumors
- PMID: 23589215
- DOI: 10.1007/s10637-013-9963-6
Phase I, dose-finding study of AZD8931, an inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling, in patients with advanced solid tumors
Abstract
Aim: AZD8931 is an oral equipotent inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling. This Phase I, open-label study evaluated the safety, tolerability, and pharmacokinetics of multiple ascending doses of AZD8931 in patients with advanced solid tumors (NCT00637039).
Methods: Patients received AZD8931 as a single oral dose followed by 4 days of observation, then twice-daily dosing for 21 consecutive days. Using a standard 3 + 3 design, AZD8931 doses were escalated from 40 mg bid until the maximum tolerated dose (MTD) was established.
Results: Twenty-eight patients received AZD8931 (n = 5, 40 mg bid; n = 8, 80 mg bid; n = 6, 160 mg bid; n = 6, 240 mg bid; n = 3, 300 mg bid). Ovary (n = 8) and breast (n = 5) were the most common primary tumor types. The most frequent adverse events were treatment-emergent cutaneous (n = 27) and diarrhea (n = 21). Dose-limiting toxicities (DLTs) were identified in one patient in the 240 mg bid cohort (Grade 3 rash) and two patients in the 300 mg bid cohort (Grade 3 and 4 diarrhea). The pharmacokinetic profile of AZD8931 supported twice-daily dosing. AZD8931 was rapidly absorbed (median tmax 1-3 h), was well distributed and had moderate to high clearance with an elimination half-life of approximately 11 h. Exposure appeared to increase approximately proportionally with dose up to 160 mg. Of 21 patients evaluable for response at day 21, 12 had stable disease and nine had disease progression.
Conclusion: The MTD of AZD8931 determined from the 21-day DLT period was 240 mg bid, although more long-term data are needed to confirm a dose of AZD8931 suitable for chronic treatment.
Similar articles
-
Inhibition of EGFR, HER2 and HER3 signaling with AZD8931 alone and in combination with paclitaxel: phase i study in Japanese patients with advanced solid malignancies and advanced breast cancer.Invest New Drugs. 2014 Oct;32(5):946-54. doi: 10.1007/s10637-014-0112-7. Epub 2014 May 31. Invest New Drugs. 2014. PMID: 24875132 Clinical Trial.
-
A phase I study of AST1306, a novel irreversible EGFR and HER2 kinase inhibitor, in patients with advanced solid tumors.J Hematol Oncol. 2014 Mar 11;7:22. doi: 10.1186/1756-8722-7-22. J Hematol Oncol. 2014. PMID: 24612546 Free PMC article. Clinical Trial.
-
AZD8931, an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor (EGFR), HER2, and HER3: preclinical activity in HER2 non-amplified inflammatory breast cancer models.J Exp Clin Cancer Res. 2014 May 30;33(1):47. doi: 10.1186/1756-9966-33-47. J Exp Clin Cancer Res. 2014. PMID: 24886365 Free PMC article.
-
Irreversible multitargeted ErbB family inhibitors for therapy of lung and breast cancer.Curr Cancer Drug Targets. 2015;14(9):775-93. doi: 10.2174/1568009614666141111104643. Curr Cancer Drug Targets. 2015. PMID: 25435079 Review.
-
Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases.Clin Ther. 2008 Aug;30(8):1426-47. doi: 10.1016/j.clinthera.2008.08.008. Clin Ther. 2008. PMID: 18803986 Review.
Cited by
-
Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC): A phase I dose escalating safety study and randomised dose expansion of AZD8931 in combination with oxaliplatin and capecitabine chemotherapy in patients with oesophagogastric adenocarcinoma.Eur J Cancer. 2020 Jan;124:131-141. doi: 10.1016/j.ejca.2019.10.010. Epub 2019 Nov 22. Eur J Cancer. 2020. PMID: 31765988 Free PMC article.
-
Inhibition of EGFR, HER2 and HER3 signaling with AZD8931 alone and in combination with paclitaxel: phase i study in Japanese patients with advanced solid malignancies and advanced breast cancer.Invest New Drugs. 2014 Oct;32(5):946-54. doi: 10.1007/s10637-014-0112-7. Epub 2014 May 31. Invest New Drugs. 2014. PMID: 24875132 Clinical Trial.
-
Human epidermal growth factor receptor targeted inhibitors for the treatment of ovarian cancer.Cancer Biol Med. 2018 Nov;15(4):375-388. doi: 10.20892/j.issn.2095-3941.2018.0062. Cancer Biol Med. 2018. PMID: 30766749 Free PMC article.
-
Use of a genetically engineered mouse model as a preclinical tool for HER2 breast cancer.Dis Model Mech. 2016 Feb;9(2):131-40. doi: 10.1242/dmm.023143. Epub 2015 Dec 31. Dis Model Mech. 2016. PMID: 26721874 Free PMC article.
-
Oncobox Bioinformatical Platform for Selecting Potentially Effective Combinations of Target Cancer Drugs Using High-Throughput Gene Expression Data.Cancers (Basel). 2018 Sep 29;10(10):365. doi: 10.3390/cancers10100365. Cancers (Basel). 2018. PMID: 30274248 Free PMC article.
References
Publication types
MeSH terms
Substances
Associated data
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials
Miscellaneous