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

Abstract
Background Aurora kinase overexpression or amplifications are connected rich in proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is definitely an investigational, dental, selective pan-Aurora kinase inhibitor. Methods This primary-in-human trial incorporated dose-escalation and dose-expansion phases ( ClinicalTrials.gov : NCT00858377). Dose escalation evaluated the security, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the utmost 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 cancer of the breast (TNBC), and castration-resistant and taxane- or cisplatin/etoposide-resistant cancer of the prostate (CRPC). AMG 900 was administered 4 days on/ten days off at 1-50 mg/day during escalation and also at the MTD with G-CSF during expansion. Results AMG 900 demonstrated rapid absorption with fast clearance, supporting once-daily dosing. The MTD was 25 mg/day, growing to 40 mg/day with G-CSF. Grade = 3 treatment-related adverse occasions incorporated neutropenia (37%), anemia (23%), leukopenia (14%), and thrombocytopenia (12%). During dose expansion, 3/29 (10.3%, 95% CI: 2.%-28.%) evaluable patients with ovarian cancer experienced partial response by central imaging per RECIST 1.1 median time period of response was 24.1 days (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 taken care of immediately treatment. No objective responses were noticed in patients with TNBC or CRPC per RECIST 1.1. Conclusions AMG 900 40 mg/day with G-CSF had manageable toxicity and shown single-agent activity in patients with heavily pretreated, AMG-900 chemotherapy-resistant ovarian cancer.