Cancer Chemotherapy and Pharmacology

, Volume 80, Issue 5, pp 1005–1012 | Cite as

Phase I study of a chloroquine–gemcitabine combination in patients with metastatic or unresectable pancreatic cancer

  • Panagiotis Samaras
  • Marina Tusup
  • Thi Dan Linh Nguyen-Kim
  • Burkhardt Seifert
  • Helga Bachmann
  • Roger von Moos
  • Alexander Knuth
  • Steve Pascolo
Original Article



Following a previously published pre-clinical validation, this phase I study evaluated the safety, maximum tolerated dose, anti-tumour activity and immune status of a gemcitabine–chloroquine combination as a first- or late-line treatment in patients with metastatic or unresectable pancreatic cancer.


In this 3 + 3 dose escalation study, patients received a single weekly standard dose of intravenous gemcitabine, followed by single weekly oral intake of 100, 200 or 300 mg of chloroquine. Tumour response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. Immune status was evaluated by RT-PCR to measure the relative expression of immune-related genes in peripheral blood mononuclear cells (PBMCs).


Overall, nine patients [median age 72 years; interquartile range (IQR), 68–78 years] were treated. No dose-limiting toxicities as defined in the protocol were observed. Three patients experienced partial response, and two patients had stable disease. The median time to progression was 4 months (95% CI 0.8–7.2), and the median overall survival was 7.6 months (95% CI 5.3–9.9). Among 86 assayed immune genes, three were significantly differentially expressed in PBMCs from responding versus non-responding patients: interferon-gamma receptor-1, toll-like receptor 2, and beta-2 microglobulin.


The addition of chloroquine to gemcitabine was well tolerated and showed promising effects on the clinical response to the anti-cancer chemotherapy. Based on these initial results, the efficacy of the gemcitabine–chloroquine combination should be further assessed.


Chloroquine Gemcitabine Pancreatic cancer Interferon-gamma receptor-1 Toll-like receptor 2 Beta-2 microglobulin 



This work was supported by the Julius Müller Stiftung and the Kurt und Senta Hermann Stiftung.

Compliance with ethical standards


This study was funded by the University Hospital of Zürich, the Julius Müller Stiftung and the Kurt und Senta Hermann Stiftung.

Conflict of interest

Authors Samaras, Nguyen-Kim, Seifert, Bachmann, Knuth and Pascolo declare that they have no conflict of interest. Author von Moos is a participant in an advisory board of Elli Lilly.


This article does not contain any studies with animals performed by any of the authors.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the local Ethics Committee and Swissmedic ( identifier: NCT01777477) and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

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

Supplementary material

280_2017_3446_MOESM1_ESM.xlsx (14 kb)
Supplementary material 1 (XLSX 13 KB)
280_2017_3446_MOESM2_ESM.xlsx (20 kb)
Supplementary material 2 (XLSX 19 KB)


  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer Statistics (2017) CA Cancer J Clin 67(1):7–30CrossRefPubMedGoogle Scholar
  2. 2.
    Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6):2403–2413CrossRefPubMedGoogle Scholar
  3. 3.
    Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y et al (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364(19):1817–1825CrossRefPubMedGoogle Scholar
  4. 4.
    Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M et al (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369(18):1691–1703CrossRefGoogle Scholar
  5. 5.
    Schlitzer M (2007) Malaria chemotherapeutics part I: History of antimalarial drug development, currently used therapeutics, and drugs in clinical development. ChemMedChem 2(7):944–986CrossRefPubMedGoogle Scholar
  6. 6.
    Lee SJ, Silverman E, Bargman JM (2011) The role of antimalarial agents in the treatment of SLE and lupus nephritis. Nat Rev Nephrol 7(12):718–729CrossRefPubMedGoogle Scholar
  7. 7.
    Pascolo S (2016) Time to use a dose of Chloroquine as an adjuvant to anti-cancer chemotherapies. Eur J Pharmacol 771:139–144CrossRefPubMedGoogle Scholar
  8. 8.
    Accapezzato D, Visco V, Francavilla V, Molette C, Donato T, Paroli M et al (2005) Chloroquine enhances human CD8 + T cell responses against soluble antigens in vivo. J Exp Med 202(6):817–828CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Solomon VR, Lee H (2009) Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies. Eur J Pharmacol 625(1–3):220–233CrossRefPubMedGoogle Scholar
  10. 10.
    Briceno E, Calderon A, Sotelo J (2007) Institutional experience with chloroquine as an adjuvant to the therapy for glioblastoma multiforme. Surg Neurol 67(4):388–391CrossRefPubMedGoogle Scholar
  11. 11.
    Sotelo J, Briceno E, Lopez-Gonzalez MA (2006) Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 144(5):337–343CrossRefPubMedGoogle Scholar
  12. 12.
    Buch IN, Munz H, Pascolo C (2016) S. Schedule-dependent synergy of chloroquine with chemotherapy for anti-cancer treatment. Cancer Res Oncol 2(2):8Google Scholar
  13. 13.
    Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G (2008) Immunological aspects of cancer chemotherapy. Nat Rev Immunol 8(1):59–73CrossRefPubMedGoogle Scholar
  14. 14.
    Jang CH, Choi JH, Byun MS, Jue DM (2006) Chloroquine inhibits production of TNF-alpha, IL-1beta and IL-6 from lipopolysaccharide-stimulated human monocytes/macrophages by different modes. Rheumatology 45(6):703–710CrossRefPubMedGoogle Scholar
  15. 15.
    Thome R, Moraes AS, Bombeiro AL, Farias Ados S, Francelin C, da Costa TA et al (2013) Chloroquine treatment enhances regulatory T cells and reduces the severity of experimental autoimmune encephalomyelitis. PLoS One 8(6):e65913CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Abiko K, Matsumura N, Hamanishi J, Horikawa N, Murakami R, Yamaguchi K et al (2015) IFN-gamma from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br J Cancer 112(9):1501–1509CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Alberts DS, Marth C, Alvarez RD, Johnson G, Bidzinski M, Kardatzke DR et al (2008) Randomized phase 3 trial of interferon gamma-1b plus standard carboplatin/paclitaxel versus carboplatin/paclitaxel alone for first-line treatment of advanced ovarian and primary peritoneal carcinomas: results from a prospectively designed analysis of progression-free survival. Gynecol Oncol 109(2):174–181CrossRefPubMedGoogle Scholar
  18. 18.
    Yang HZ, Cui B, Liu HZ, Mi S, Yan J, Yan HM et al (2009) Blocking TLR2 activity attenuates pulmonary metastases of tumor. PLoS One 4(8):e6520CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Department of OncologyUniversity Hospital of ZürichZurichSwitzerland
  2. 2.Department of DermatologyUniversity Hospital of ZürichZurichSwitzerland
  3. 3.Department of Diagnostic and Interventional RadiologyUniversity Hospital of ZürichZurichSwitzerland
  4. 4.Department of Biostatistics at the Epidemiology, Biostatistics and Prevention InstituteUniversity of ZürichZurichSwitzerland
  5. 5.National Center for Cancer Care and Research NCCCRHamad Medical CorporationDohaQatar
  6. 6.Department of DermatologyUniversity Hospital of ZürichZurichSwitzerland

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