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Phase I study combining the aurora kinase a inhibitor alisertib with mFOLFOX in gastrointestinal cancer

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Summary

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/m2) and oxaliplatin (85 mg/m2) on Day 2 followed by continuous 46-h 5-FU (2400 mg/m2) 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/m2 oxaliplatin and 2400 mg/m2 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.

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Acknowledgements

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.

Funding

We would like to thank the National Cancer Institute Clinical Trials Evaluation Program (NCI Trial #9842), the Vanderbilt-Ingram Cancer Center (P30 CA068485), and the National Institutes of Health (UM1 CA186689) for sponsoring this study.

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Authors and Affiliations

  1. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Vanderbilt University, 2220 Pierce Avenue, PRB 777, Nashville, TN, 37232, USA

    Laura W. Goff, Jennifer G. Whisenant, Tatsuki Koyama, Safia N. Salaria & Jordan D. Berlin

  2. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Laura W. Goff, Jennifer G. Whisenant & Jordan D. Berlin

  3. Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA

    Nilofer S. Azad & Roisin Connolly

  4. Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA

    Stacey Stein & Patricia M. LoRusso

  5. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA

    Tatsuki Koyama

  6. Karmanos Cancer Institute, Detroit, MI, USA

    Ulka Vaishampayan & Amy Weise

  7. Rutgers Canter Institute, New Brunswick, NJ, USA

    Howard Hochster

  8. University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA

    Wael El-Rifai

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  1. Laura W. Goff
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Correspondence to Laura W. Goff.

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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.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained for all individual participants included in the study.

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The original version of this article was revised: The authors would like to note that the investigator affiliations have been corrected to reflect the actual affiliations of each author. The authors would also like to note an amendment to the first name of the second author.

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Goff, L.W., Azad, N.S., Stein, S. et al. Phase I study combining the aurora kinase a inhibitor alisertib with mFOLFOX in gastrointestinal cancer. Invest New Drugs 37, 315–322 (2019). https://doi.org/10.1007/s10637-018-0663-0

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