Phase II trial of metformin and paclitaxel for patients with gemcitabine-refractory advanced adenocarcinoma of the pancreas

Maria Ignez Braghiroli, Anezka C R de Celis Ferrari, Tulio Eduardo Pfiffer, Alexandra Kichfy Alex, Daniela Nebuloni, Allyne S Carneiro, Fernanda Caparelli, Luiz Senna, Juliana Lobo, Paulo Marcelo Hoff, Rachel P Riechelmann, Maria Ignez Braghiroli, Anezka C R de Celis Ferrari, Tulio Eduardo Pfiffer, Alexandra Kichfy Alex, Daniela Nebuloni, Allyne S Carneiro, Fernanda Caparelli, Luiz Senna, Juliana Lobo, Paulo Marcelo Hoff, Rachel P Riechelmann

Abstract

Background: In patients with adenocarcinoma of the pancreas, there are no standard second-line regimens. Many pre-clinical studies have shown that metformin alone or when combined with paclitaxel has antitumour effects on this tumour. We have tested here the combination of paclitaxel and metformin for patients with gemcitabine-refractory pancreatic cancer.

Methods: An uncontrolled phase II trial was carried out based on a two-stage Simon's design, with metformin and paclitaxel for patients with locally advanced or metastatic pancreatic cancer whose disease had progressed during first line treatment with a gemcitabine-based regimen. The primary endpoint was the disease control rate at eight weeks as per response evaluation criteria in solid tumours (RECIST) 1.1. Patients received paclitaxel 80 mg/m(2) weekly for three weeks every 28 days and metformin 850 mg p.o. t.i.d. continuously until progression or intolerance state was reached.

Results: Twenty patients were enrolled from July 2011 to January 2014: N = 6 (31.6%) achieved the primary endpoint, with all presenting stable disease. Median overall survival (OS) was 128 days (range 17-697) and the median progression free survival (PFS) was 44 days (range 14-210). Eight patients (40%) presented treatment-related G3-4 toxicities with the most common one being diarrhoea.

Conclusions: Despite the encouraging pre-clinical evidence of the antitumour activity of metformin in adenocarcinoma of the pancreas, the primary endpoint of the disease control rate was not met. Besides, the treatment combination was poorly tolerated and could not be studied further. This study highlights the importance of performing clinical trials to reassure preclinical or observational data.

Keywords: metformin; pancreas adenocarcinoma.

References

    1. Conroy T, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25. doi: 10.1056/NEJMoa1011923.
    1. Oettle H, et al. Second-Line Oxaliplatin, Folinic Acid, and Fluorouracil Versus Folinic Acid and Fluorouracil Alone for Gemcitabine-Refractory Pancreatic Cancer: Outcomes From the CONKO-003 Trial. J Clin Oncol. 2014;32(23):2423–9. doi: 10.1200/JCO.2013.53.6995.
    1. Von Hoff D, et al., editors. Ann Oncol. Barcelona Spain: 2014. NAPOLI-1 Randomized phase 3 study of mm-398 (nal-iri), with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin, in metastatic pancreatic cancer progressed on or following gemcitabine-based therapy. ESMO 16th World Congress on Gastrointestinal Cancer.
    1. Yin M, et al. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncologist. 2013;18(12):1248–55. doi: 10.1634/theoncologist.2013-0111.
    1. Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1996;81(11):4059–67.
    1. Dowling RJ, et al. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res. 2007;67(22):10804–12. doi: 10.1158/0008-5472.CAN-07-2310.
    1. Nair V, et al. Metformin inhibits pancreatic cancer cell and tumor growth and downregulates Sp transcription factors. Carcinogenesis. 2013;34(12):2870–9. doi: 10.1093/carcin/bgt231.
    1. Karnevi E, et al. Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells. BMC Cancer. 2012;13:235. doi: 10.1186/1471-2407-13-235.
    1. Kisfalvi K, et al. Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res. 2009;69(16):6539–45. doi: 10.1158/0008-5472.CAN-09-0418.
    1. Zhang P, et al. Association of metformin use with cancer incidence and mortality: a meta-analysis. Cancer Epidemiol. 2013;37(3):207–18. doi: 10.1016/j.canep.2012.12.009.
    1. Sadeghi N, et al. Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res. 2012;18(10):2905–12. doi: 10.1158/1078-0432.CCR-11-2994.
    1. Hanna RK, et al. Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. Gynecol Oncol. 2012;125(2):458–69. doi: 10.1016/j.ygyno.2012.01.009.
    1. Rocha GZ, et al. Metformin amplifies chemotherapy-induced AMPK activation and antitumoral growth. Clin Cancer Res. 2011;17(12):3993–4005. doi: 10.1158/1078-0432.CCR-10-2243.
    1. Rahma OE, et al. Second-line treatment in advanced pancreatic cancer: a comprehensive analysis of published clinical trials. Ann Oncol. 2013;24(8):1972–9. doi: 10.1093/annonc/mdt166.
    1. Von Hoff DD, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–703. doi: 10.1056/NEJMoa1304369.
    1. Katopodis O, et al. Second-line chemotherapy with capecitabine (Xeloda) and docetaxel (Taxotere) in previously treated, unresectable adenocarcinoma of pancreas: the final results of a phase II trial. Cancer Chemother Pharmacol. 2011;67(2):361–8. doi: 10.1007/s00280-010-1329-6.
    1. Hosein PJ, et al. A phase II trial of nab-Paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol. 2013;36(2):151–6. doi: 10.1097/COC.0b013e3182436e8c.
    1. Wilmink J, et al., editors. J Clin Oncol. Chicago: 2014. A phase II randomized, placebo controlled study to evaluate the efficacy of the combination of gemcitabine, erlotinib, and metformin in patients with locally advanced or metastatic pancreatic cancer. ASCO Annual Meeting.
    1. Lonardo E, et al. Metformin targets the metabolic achilles heel of human pancreatic cancer stem cells. PLoS One. 2013;8(10):e76518. doi: 10.1371/journal.pone.0076518.
    1. Jiao Y, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331(6021):1199–203. doi: 10.1126/science.1200609.

Source: PubMed

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