A phase 1, first-in-human study of AMG 900, an orally administered pan-Aurora kinase inhibitor, in adult patients with advanced solid tumors
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Background Aurora kinase overexpression or amplifications are associated with high proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is an investigational, oral, selective pan-Aurora kinase inhibitor. Methods This first-in-human trial included dose-escalation and dose-expansion phases (ClinicalTrials.gov: NCT00858377). Dose escalation evaluated the safety, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the maximum tolerated dose (MTD) with/without granulocyte colony-stimulating factor (G-CSF) prophylaxis. Dose expansion evaluated clinical activity in three tumor types: taxane- and platinum-resistant ovarian cancer, taxane-resistant triple-negative breast cancer (TNBC), and castration-resistant and taxane- or cisplatin/etoposide–resistant prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at 1–50 mg/day during escalation and at the MTD with G-CSF during expansion. Results AMG 900 showed rapid absorption with fast clearance, supporting once-daily dosing. The MTD was 25 mg/day, increasing to 40 mg/day with G-CSF. Grade ≥ 3 treatment-related adverse events included neutropenia (37%), anemia (23%), leukopenia (14%), and thrombocytopenia (12%). During dose expansion, 3/29 (10.3%, 95% CI: 2.0%–28.0%) evaluable patients with ovarian cancer experienced partial response by central imaging per RECIST 1.1; median duration of response was 24.1 weeks (95% CI: 16.1–34.1). Seven patients (24.1%, 95% CI: 10.3%–43.5%) experienced partial response per Gynecologic Cancer InterGroup criteria; 5/9 patients positive for p53 expression responded to treatment. No objective responses were observed in patients with TNBC or CRPC per RECIST 1.1. Conclusions AMG 900 40 mg/day with G-CSF had manageable toxicity and demonstrated single-agent activity in patients with heavily pretreated, chemotherapy-resistant ovarian cancer.
KeywordsAMG 900 Antimitotic Aurora kinase pan-Aurora kinase inhibitor
This study was sponsored by Amgen Inc. Funding for writing of this manuscript was provided by Amgen Inc. Micah Robinson, PhD (Amgen Inc.), as well as Miranda Tradewell, PhD, James Balwit, MS, CMPP, and Rick Davis, MS (Complete Healthcare Communications, LLC; on behalf of Amgen Inc.) assisted with writing the manuscript.
Compliance with ethical standards
Disclosure of potential conflicts of interest
Michael Carducci reports research funding from Amgen to his institution during the conduct of this study. Sara Hurvitz reports a grant from OBI Pharma during the conduct of this study, and grants/research support from Amgen Inc., Bayer, BI Pharma, Genentech, GSK, Lilly, Novartis, Pfizer, Roche, PUMA, Merrimack, Medivation, Dignitana, OBI Pharma, Biomarin, Cascadian, and Seattle Genetics outside the submitted work. Erik Rasmussen, Gloria Juan, Vincent Chow, and Gregory Friberg are employees of Amgen Inc. and hold Amgen stock. Florian Vogl was an employee of Amgen Inc. at the time this work was conducted and holds stock in Amgen Inc. Erick Gamelin was an employee of Amgen Inc. at the time this work was conducted. Jayesh Desai has received research grants from Novartis, Bionomics, and Roche/Genentech and has received fees for consulting from Amgen, Novartis, Bionomics, Lilly, and Eisai. Montaser Shaheen, Ben Markman, Daruka Mahadevan, Dusan Kotasek, and Oscar Goodman declare they have no conflicts of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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