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 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.

Conflict of interest statement

Disclosure of potential conflicts of interest Montaser Shaheen, Ben Markman, Daruka Mahadevan, Dusan Kotasek, and Oscar Goodman declare they have no conflicts of interest.

Figures

Fig. 1

Maximum percentage tumor reduction and response (by RECIST 1.1) by individual patient for (a) all patients with ovarian tumors from the dose-escalation and -expansion phases. Central read data are available for 31 of 33 patients; plot includes four patients with ovarian cancer from the dose-escalation phase; aProgressive disease by new lesion; bStable disease by RECIST 1.1 (CA 125 was not available); cPatient still on treatment at data cutoff. Arrows represent the best response for patients whose tumor change was not visible because of being near 0. b Patients with triple-negative breast cancer in the dose-expansion phase. Central read data are available for 11 of 14 patients; aProgressive disease by new lesion; bProgressive disease of nontarget lesion. c Patients with castration-resistant prostate cancer in the dose-expansion phase. Central read data are available for 10 of 12 patients. Data cutoff: December 31, 2014. SLD = sum of longest diameters

Fig. 2

Progression-free survival in patients with ovarian cancer as determined by (a) RECIST 1.1 or by (b) Gynecologic Cancer InterGroup criteria (RECIST 1.1 and CA 125). NE = not estimable