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

Ann Surg Oncol. 2015 Dec;22(13):4402-10. doi: 10.1245/s10434-015-4566-4. Epub 2015 Apr 24.

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.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology
  • Adult
  • Aged
  • Aged, 80 and over
  • Antimetabolites, Antineoplastic / therapeutic use
  • Antirheumatic Agents / therapeutic use
  • Autophagy / drug effects*
  • Biomarkers / metabolism
  • CA-19-9 Antigen / metabolism
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use
  • Drug Therapy, Combination
  • Female
  • Follow-Up Studies
  • Humans
  • Hydroxychloroquine / therapeutic use*
  • Immunoenzyme Techniques
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / pathology
  • Prognosis
  • Prospective Studies
  • Safety
  • Survival Rate

Substances

  • Antimetabolites, Antineoplastic
  • Antirheumatic Agents
  • Biomarkers
  • CA-19-9 Antigen
  • Deoxycytidine
  • Hydroxychloroquine
  • gemcitabine

Supplementary concepts

  • Pancreatic Carcinoma