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04-10-2017 | Pancreatic cancer | Article

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

Journal: Cancer Chemotherapy and Pharmacology

Authors: Panagiotis Samaras, Marina Tusup, Thi Dan Linh Nguyen-Kim, Burkhardt Seifert, Helga Bachmann, Roger von Moos, Alexander Knuth, Steve Pascolo

Publisher: Springer Berlin Heidelberg

Abstract

Purpose

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.

Methods

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).

Results

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.

Conclusions

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.

Siegel RL, Miller KD, Jemal A. Cancer Statistics (2017) CA Cancer J Clin 67(1):7–30CrossRefPubMed

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):2403–2413CrossRefPubMed

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):1817–1825CrossRefPubMed

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):1691–1703CrossRef

Schlitzer M (2007) Malaria chemotherapeutics part I: History of antimalarial drug development, currently used therapeutics, and drugs in clinical development. ChemMedChem 2(7):944–986CrossRefPubMed

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):718–729CrossRefPubMed

Pascolo S (2016) Time to use a dose of Chloroquine as an adjuvant to anti-cancer chemotherapies. Eur J Pharmacol 771:139–144CrossRefPubMed

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):817–828CrossRefPubMedPubMedCentral

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):220–233CrossRefPubMed

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):388–391CrossRefPubMed

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):337–343CrossRefPubMed

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):8

13.

Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G (2008) Immunological aspects of cancer chemotherapy. Nat Rev Immunol 8(1):59–73CrossRefPubMed

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):703–710CrossRefPubMed

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):e65913CrossRefPubMedPubMedCentral

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):1501–1509CrossRefPubMedPubMedCentral

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):174–181CrossRefPubMed

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):e6520CrossRefPubMedPubMedCentral