Safety and Biologic Response of Pre-operative Autophagy Inhibition in Combination with Gemcitabine in Patients with Pancreatic Adenocarcinoma

Brian A. Boone, Nathan Bahary, Amer H. Zureikat, A. James Moser, Daniel P. Normolle, Wen Chi Wu, Aatur D. Singhi, Phillip Bao, David L. Bartlett, Lance A. Liotta, Virginia Espina, Patricia Loughran, Michael T. Lotze, Herbert J. Zeh

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

Purpose: Autophagy is a cell survival mechanism that plays a critical role in pancreatic carcinogenesis. Murine studies have previously demonstrated that treatment with the late-autophagy inhibitor chloroquine in combination with chemotherapy limited tumor growth. Methods: In this phase 1/2 trial, we examined treatment with hydroxychloroquine (HCQ) and gemcitabine for patients with pancreatic adenocarcinoma. The primary endpoints were safety and tolerability, evaluated by Storer’s dose escalation design. Secondary endpoints were CA 19-9 biomarker response, R0 resection rates, survival, and correlative studies of autophagy. Results: Thirty-five patients were enrolled. There were no dose-limiting toxicities and no grade 4/5 events related to treatment. Nineteen patients (61 %) had a decrease in CA 19-9 after treatment. Twenty-nine patients (94 %) underwent surgical resection as scheduled, with a 77 % R0 resection rate. Median overall survival was 34.8 months (95 % confidence interval, 11.57 to not reached). Patients who had more than a 51 % increase in the autophagy marker LC3-II in circulating peripheral blood mononuclear cells had improvement in disease-free survival (15.03 vs. 6.9 months, p < 0.05) and overall survival (34.83 vs. 10.83 months, p < 0.05). No outcome differences were demonstrated in the 81 % of patients with abnormal p53 expression assessed by immunohistochemistry in the resected specimens. Conclusions: Preoperative autophagy inhibition with HCQ plus gemcitabine is safe and well tolerated. Surrogate biomarker responses (CA 19-9) and surgical oncologic outcomes were encouraging. p53 status was not associated with adverse outcomes.

Original languageEnglish (US)
Pages (from-to)4402-4410
Number of pages9
JournalAnnals of Surgical Oncology
Volume22
Issue number13
DOIs
StatePublished - Dec 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Surgery
  • Oncology

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    Boone, B. A., Bahary, N., Zureikat, A. H., Moser, A. J., Normolle, D. P., Wu, W. C., Singhi, A. D., Bao, P., Bartlett, D. L., Liotta, L. A., Espina, V., Loughran, P., Lotze, M. T., & Zeh, H. J. (2015). Safety and Biologic Response of Pre-operative Autophagy Inhibition in Combination with Gemcitabine in Patients with Pancreatic Adenocarcinoma. Annals of Surgical Oncology, 22(13), 4402-4410. https://doi.org/10.1245/s10434-015-4566-4