TY - JOUR
T1 - Phase I study combining the aurora kinase a inhibitor alisertib with mFOLFOX in gastrointestinal cancer
AU - Goff, Laura W.
AU - Azad, Nilofer S.
AU - Stein, Stacey
AU - Whisenant, Jennifer G.
AU - Koyama, Tatsuki
AU - Vaishampayan, Ulka
AU - Hochster, Howard
AU - Connolly, Roisin
AU - Weise, Amy
AU - LoRusso, Patricia M.
AU - Salaria, Safia N.
AU - El-Rifai, Wael
AU - Berlin, Jordan D.
N1 - Funding Information:
Conflicts of interest LWG has served as a consultant for Celgene and has institutional research funding from Astellas Pharma, Pfizer, Onxy, SunPharma, Lilly, and Bristol-Myers Squibb. SS has participated in advisory boards for Genentech Roche and Merck. HH has served as a consultant for Bayer, Genentech, and Merck. RC has received research grants from Macrogenics, Novartis, Puma Biotechnology, Merck, Merrimack, and Genentech. JB has served as a consultant for Celgene, Genentech, Aduro, Boston Biomedical, Janssen, Cornerstone, Symphogen, and Bayer and has institutional research funding from Genentech, Abbvie, Taiho, Bayer, 5Prime, Phoenix, Incyte, and Vertex. For the remaining authors, none were declared.
Funding Information:
The authors would like to thank the patients who participated in this study and their families, the study investigators, and study staff. We would also like to thank the National Cancer Institute Clinical Trials Evaluation Program (NCI Trial #9824), the Vanderbilt-Ingram Cancer Center (P30 CA068485), and the National Institutes of Health (UM1 CA186689) for sponsoring this study.
Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2019/4/15
Y1 - 2019/4/15
N2 - Overexpression and cellular mis-localization of aurora kinase A (AURKA) in gastrointestinal cancers results in chromosomal instability, activation of multiple oncogenic pathways, and inhibition of pro-apoptotic signaling. Inhibition of AURKA causes mitotic delays, severe chromosome congression, and activation of p53/p73 leading to cell death. Our preclinical data showed cooperative activity with the AURKA inhibitor alisertib and platinum agents in cell lines and xenografts, and suggested an optimal treatment window. Therefore, this study was designed to determine the maximum-tolerated dose (MTD) of alisertib in combination with modified FOLFOX (mFOLFOX), as this is a standard platinum-based therapy for gastrointestinal cancers. Standard 3 + 3 dose escalation was used, where the starting dose of alisertib was 10 mg twice daily (Days 1–3), with leucovorin (400 mg/m 2 ) and oxaliplatin (85 mg/m 2 ) on Day 2 followed by continuous 46-h 5-FU (2400 mg/m 2 ) infusion on Days 2–4 in 14-day cycles. Fourteen patients with advanced gastrointestinal cancers were enrolled and two doses explored; two patients were not evaluable for dose-limiting toxicity (DLT) and replaced. Two patients experienced DLTs at 20 mg of alisertib (Grade 3 fatigue (n = 2); Grade 3 nausea, vomiting, dehydration with hospitalization (n = 1)). MTD was 10 mg alisertib with 85 mg/m 2 oxaliplatin and 2400 mg/m 2 5-FU. Most frequent toxicities were nausea (57%), diarrhea, fatigue, neuropathy, and vomiting (43%), and anorexia and anemia (36%); most were Grade 1–2. One patient with colorectal cancer had a partial response of 12 evaluable patients, and four patients had stable disease. Alisertib in combination with mFOLFOX did not demonstrate unexpected side effects, but the regimen was only tolerable at the lowest dose investigated.
AB - Overexpression and cellular mis-localization of aurora kinase A (AURKA) in gastrointestinal cancers results in chromosomal instability, activation of multiple oncogenic pathways, and inhibition of pro-apoptotic signaling. Inhibition of AURKA causes mitotic delays, severe chromosome congression, and activation of p53/p73 leading to cell death. Our preclinical data showed cooperative activity with the AURKA inhibitor alisertib and platinum agents in cell lines and xenografts, and suggested an optimal treatment window. Therefore, this study was designed to determine the maximum-tolerated dose (MTD) of alisertib in combination with modified FOLFOX (mFOLFOX), as this is a standard platinum-based therapy for gastrointestinal cancers. Standard 3 + 3 dose escalation was used, where the starting dose of alisertib was 10 mg twice daily (Days 1–3), with leucovorin (400 mg/m 2 ) and oxaliplatin (85 mg/m 2 ) on Day 2 followed by continuous 46-h 5-FU (2400 mg/m 2 ) infusion on Days 2–4 in 14-day cycles. Fourteen patients with advanced gastrointestinal cancers were enrolled and two doses explored; two patients were not evaluable for dose-limiting toxicity (DLT) and replaced. Two patients experienced DLTs at 20 mg of alisertib (Grade 3 fatigue (n = 2); Grade 3 nausea, vomiting, dehydration with hospitalization (n = 1)). MTD was 10 mg alisertib with 85 mg/m 2 oxaliplatin and 2400 mg/m 2 5-FU. Most frequent toxicities were nausea (57%), diarrhea, fatigue, neuropathy, and vomiting (43%), and anorexia and anemia (36%); most were Grade 1–2. One patient with colorectal cancer had a partial response of 12 evaluable patients, and four patients had stable disease. Alisertib in combination with mFOLFOX did not demonstrate unexpected side effects, but the regimen was only tolerable at the lowest dose investigated.
KW - Alisertib
KW - Aurora kinase a inhibition
KW - Gastrointestinal cancers
KW - Modified FOLFOX
UR - http://www.scopus.com/inward/record.url?scp=85053459419&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053459419&partnerID=8YFLogxK
U2 - 10.1007/s10637-018-0663-0
DO - 10.1007/s10637-018-0663-0
M3 - Article
C2 - 30191522
AN - SCOPUS:85053459419
SN - 0167-6997
VL - 37
SP - 315
EP - 322
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 2
ER -