TY - JOUR
T1 - A phase 1, first-in-human study of AMG 900, an orally administered pan-Aurora kinase inhibitor, in adult patients with advanced solid tumors
AU - Carducci, Michael
AU - Shaheen, Montaser
AU - Markman, Ben
AU - Hurvitz, Sara
AU - Mahadevan, Daruka
AU - Kotasek, Dusan
AU - Goodman, Oscar B.
AU - Rasmussen, Erik
AU - Chow, Vincent
AU - Juan, Gloria
AU - Friberg, Gregory R.
AU - Gamelin, Erick
AU - Vogl, Florian D.
AU - Desai, Jayesh
N1 - Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
KW - AMG 900
KW - Antimitotic
KW - Aurora kinase
KW - pan-Aurora kinase inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85049591801&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85049591801&partnerID=8YFLogxK
U2 - 10.1007/s10637-018-0625-6
DO - 10.1007/s10637-018-0625-6
M3 - Article
C2 - 29980894
AN - SCOPUS:85049591801
SN - 0167-6997
VL - 36
SP - 1060
EP - 1071
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 6
ER -