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Invest New Drugs. 2018 Dec;36(6):1060-1071. doi: 10.1007/s10637-018-0625-6. Epub 2018 Jul 7.

A phase 1, first-in-human study of AMG 900, an orally administered pan-Aurora kinase inhibitor, in adult patients with advanced solid tumors.

Author information

1
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1M59 Bunting Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD, 21287, USA. Carducci@jhmi.edu.
2
University of Arizona Cancer Center, Tucson, AZ, USA.
3
Monash Health, Melbourne, VIC, Australia.
4
University of California Los Angeles, Los Angeles, CA, USA.
5
Adelaide Cancer Centre, Kurralta Park, Adelaide, SA, Australia.
6
Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA.
7
Amgen Inc., Thousand Oaks, CA, USA.
8
Royal Melbourne Hospital, Parkville, VIC, Australia.

Abstract

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.

KEYWORDS:

AMG 900; Antimitotic; Aurora kinase; pan-Aurora kinase inhibitor

PMID:
29980894
DOI:
10.1007/s10637-018-0625-6

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