Brian A Boone1, Nathan Bahary2, Amer H Zureikat1, A James Moser3, Daniel P Normolle4, Wen-Chi Wu4, Aatur D Singhi5, Phillip Bao1, David L Bartlett1, Lance A Liotta6, Virginia Espina6, Patricia Loughran1, Michael T Lotze7, Herbert J Zeh8. 1. Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. 2. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. 3. Institute for Hepatobiliary and Pancreatic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. 4. Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA. 5. Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA. 6. Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA. 7. Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. lotzemt@upmc.edu. 8. Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. zehxhx@upmc.edu.
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.
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.
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