Investigational New Drugs

, Volume 30, Issue 4, pp 1531–1539 | Cite as

Phase I study of axitinib (AG-013736) in combination with gemcitabine in patients with advanced pancreatic cancer

  • Jean-Philippe SpanoEmail author
  • Malcolm J. Moore
  • Yazdi K. Pithavala
  • Alejandro D. Ricart
  • Sinil Kim
  • Olivier Rixe


Purpose Axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, is under investigation for treatment of various solid tumors. The safety and pharmacokinetics of axitinib in combination with gemcitabine in patients with advanced pancreatic cancer was evaluated in the phase I portion of this trial. The randomized phase II portion was reported separately. Patients and methods Patients with advanced pancreatic cancer who had received no prior chemotherapy were eligible for this study. Pharmacokinetic profiles of the drugs were obtained on cycle (C) 1 day (D) 1 (gemcitabine alone 1,000 mg/m2), C1D14 (steady state, axitinib alone 5 mg twice daily [BID]), and C1D15 (gemcitabine plus steady-state axitinib). Adverse events were monitored weekly at the clinic. Results Eight patients participated in the phase IB portion of the trial. Patients received gemcitabine on D1, D8, and D15 and continuous axitinib in a 28 day-cycle beginning C1D3. There was no dose-limiting toxicity. Common treatment-related adverse events included fatigue, diarrhea, dysphonia, and hypertension. Myelosuppression was similar to gemcitabine monotherapy. No apparent major pharmacokinetic interactions between gemcitabine and axitinib were observed. Of six patients evaluable for efficacy, three had confirmed partial responses. Conclusions Axitinib (5 mg BID) and gemcitabine (1,000 mg/m2) were well tolerated when administered together, without any pharmacokinetic interactions, and showed encouraging antitumor activity.


Axitinib Gemcitabine Combination Pharmacokinetics Pancreatic cancer 



The authors thank Prof. Laurent Hannoun, Hôpital de la Pitié Salpêtrière, Paris, France, for his critical contributions to the care of the patients enrolled in this study. Under guidance of authors, medical writing assistance was provided by Mukund Nori, PhD, MBA, CMPP at UBC Scientific Solutions and funded by Pfizer Inc. The authors thank Gamal ElSawah, MD, Pfizer Medical Affairs for his review of the manuscript. This study was sponsored by Pfizer Inc.


  1. 1.
    American Cancer Society (2010) Cancer facts & figures 2010. Accessed July 14, 2010
  2. 2.
    Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin caac.20073. doi: 10.3322/caac.20073
  3. 3.
    American Cancer Society (2007) Global cancer facts & figures 2007. Accessed February 11, 2010
  4. 4.
    Saif MW (2008) New developments in the treatment of pancreatic cancer. Highlights from the “44th ASCO Annual Meeting”. Chicago, IL, USA. May 30–June 3, 2008. JOP 9:391–397PubMedGoogle Scholar
  5. 5.
    Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (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 15:2403–2413PubMedGoogle Scholar
  6. 6.
    Berlin JD, Catalano P, Thomas JP, Kugler JW, Haller DG, Benson AB 3rd (2002) Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group trial E2297. J Clin Oncol 20:3270–3275. doi: 10.1200/JCO.2002.11.149 CrossRefPubMedGoogle Scholar
  7. 7.
    Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schuller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Kohne CH, Mingrone W, Stemmer SM, Tamas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W (2007) Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol 25:2212–2217. doi: 10.1200/JCO.2006.09.0886 CrossRefPubMedGoogle Scholar
  8. 8.
    Bramhall SR, Schulz J, Nemunaitis J, Brown PD, Baillet M, Buckels JA (2002) A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 87:161–167. doi: 10.1038/sj.bjc.6600446 CrossRefPubMedGoogle Scholar
  9. 9.
    Abou-Alfa GK, Letourneau R, Harker G, Modiano M, Hurwitz H, Tchekmedyian NS, Feit K, Ackerman J, De Jager RL, Eckhardt SG, O’Reilly EM (2006) Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J Clin Oncol 24:4441–4447. doi: 10.1200/JCO.2006.07.0201 CrossRefPubMedGoogle Scholar
  10. 10.
    Rocha Lima CM, Green MR, Rotche R, Miller WH Jr, Jeffrey GM, Cisar LA, Morganti A, Orlando N, Gruia G, Miller LL (2004) Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 22:3776–3783. doi: 10.1200/JCO.2004.12.082 CrossRefPubMedGoogle Scholar
  11. 11.
    Van Cutsem E, van de Velde H, Karasek P, Oettle H, Vervenne WL, Szawlowski A, Schoffski P, Post S, Verslype C, Neumann H, Safran H, Humblet Y, Perez Ruixo J, Ma Y, Von Hoff D (2004) Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 22:1430–1438. doi: 10.1200/JCO.2004.10.112 CrossRefPubMedGoogle Scholar
  12. 12.
    Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, Andre T, Zaniboni A, Ducreux M, Aitini E, Taieb J, Faroux R, Lepere C, de Gramont A (2005) Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 23:3509–3516. doi: 10.1200/JCO.2005.06.023 CrossRefPubMedGoogle Scholar
  13. 13.
    Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schonekas H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R (2006) Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 24:3946–3952. doi: 10.1200/JCO.2005.05.1490 CrossRefPubMedGoogle Scholar
  14. 14.
    Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966. doi: 10.1200/JCO.2006.07.9525 CrossRefPubMedGoogle Scholar
  15. 15.
    Philip PA, Benedetti J, Corless CL, Wong R, O’Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD (2010) Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-Directed Intergroup Trial S0205. J Clin Oncol. doi: 10.1200/jco.2009.25.7550
  16. 16.
    Korc M (2003) Pathways for aberrant angiogenesis in pancreatic cancer. Mol Cancer 2:8. doi: 10.1186/1476-4598-2-8 CrossRefPubMedGoogle Scholar
  17. 17.
    Chung GG, Yoon HH, Zerkowski MP, Ghosh S, Thomas L, Harigopal M, Charette LA, Salem RR, Camp RL, Rimm DL, Burtness BA (2006) Vascular endothelial growth factor, FLT-1, and FLK-1 analysis in a pancreatic cancer tissue microarray. Cancer 106:1677–1684. doi: 10.1002/cncr.21783 CrossRefPubMedGoogle Scholar
  18. 18.
    Hu-Lowe DD, Zou HY, Grazzini ML, Hallin ME, Wickman GR, Amundson K, Chen JH, Rewolinski DA, Yamazaki S, Wu EY, McTigue MA, Murray BW, Kania RS, O’Connor P, Shalinsky DR, Bender SL (2008) Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res 14:7272–7283. doi: 10.1158/1078-0432.CCR-08-0652 CrossRefPubMedGoogle Scholar
  19. 19.
    Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, Pithavala YK, Reich SD, Freddo JL, Wilding G (2005) Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol 23:5474–5483. doi: 10.1200/JCO.2005.04.192 CrossRefPubMedGoogle Scholar
  20. 20.
    Schiller JH, Larson T, Ou SH, Limentani S, Sandler A, Vokes E, Kim S, Liau K, Bycott P, Olszanski AJ, von Pawel J (2009) Efficacy and safety of axitinib in patients with advanced non-small-cell lung cancer: results from a phase II study. J Clin Oncol 27:3836–3841. doi: 10.1200/JCO.2008.20.8355 CrossRefPubMedGoogle Scholar
  21. 21.
    Rixe O, Bukowski RM, Michaelson MD, Wilding G, Hudes GR, Bolte O, Motzer RJ, Bycott P, Liau KF, Freddo J, Trask PC, Kim S, Rini BI (2007) Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol 8:975–984. doi: 10.1016/S1470-2045(07)70285-1 CrossRefPubMedGoogle Scholar
  22. 22.
    Cohen EE, Rosen LS, Vokes EE, Kies MS, Forastiere AA, Worden FP, Kane MA, Sherman E, Kim S, Bycott P, Tortorici M, Shalinsky DR, Liau KF, Cohen RB (2008) Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol 26:4708–4713. doi: 10.1200/JCO.2007.15.9566 CrossRefPubMedGoogle Scholar
  23. 23.
    Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, Langer C, Murphy B, Cumberlin R, Coleman CN, Rubin P (2003) CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 13:176–181. doi: 10.1016/S1053-4296(03)00031-6 CrossRefPubMedGoogle Scholar
  24. 24.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Nat Cancer Inst 92:205–216. doi: 10.1093/jnci/92.3.205 CrossRefPubMedGoogle Scholar
  25. 25.
    Heinemann V, Boeck S, Hinke A, Labianca R, Louvet C (2008) Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer 8:82. doi: 10.1186/1471-2407-8-82 CrossRefPubMedGoogle Scholar
  26. 26.
    Dragovich T, Huberman M, Von Hoff DD, Rowinsky EK, Nadler P, Wood D, Hamilton M, Hage G, Wolf J, Patnaik A (2007) Erlotinib plus gemcitabine in patients with unresectable pancreatic cancer and other solid tumors: phase IB trial. Cancer Chemother Pharmacol 60:295–303. doi: 10.1007/s00280-006-0389-0 CrossRefPubMedGoogle Scholar
  27. 27.
    Spano JP, Chodkiewicz C, Maurel J, Wong R, Wasan H, Barone C, Letourneau R, Bajetta E, Pithavala Y, Bycott P, Trask P, Liau K, Ricart AD, Kim S, Rixe O (2008) Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet 371:2101–2108. doi: 10.1016/S0140-6736(08)60661-3 CrossRefPubMedGoogle Scholar
  28. 28.
    Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, Nowak B, Mineishi S, Tarassoff P, Satterlee W, Raber MN et al (1991) A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9:491–498PubMedGoogle Scholar
  29. 29.
    Yilmaz B, Kadioglu YY, Aksoy Y (2004) Investigation of the pharmacokinetics of gemcitabine and 2′,2′-difluorodeoxyuridine in human plasma by liquid chromatography. Anal Biochem 332:234–237. doi: 10.1016/j.ab.2004.05.059 CrossRefPubMedGoogle Scholar
  30. 30.
    Delaloge S, Llombart A, Di Palma M, Tourani JM, Turpin F, Ni L, Forgue ST, Le Chevalier T (2004) Gemcitabine in patients with solid tumors and renal impairment: a pharmacokinetic phase I study. Am J Clin Oncol 27:289–293CrossRefPubMedGoogle Scholar
  31. 31.
    Kindler HL, Ioka T, Richel DJ, Bennouna J, Letourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E (2011) Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol 12:256–262. doi: 10.1016/S1470-2045(11)70004-3 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Jean-Philippe Spano
    • 1
    Email author
  • Malcolm J. Moore
    • 2
  • Yazdi K. Pithavala
    • 3
  • Alejandro D. Ricart
    • 4
  • Sinil Kim
    • 4
  • Olivier Rixe
    • 1
    • 5
  1. 1.Groupe Hospitalier Pitié-SalpêtrièreParis Cedex 13France
  2. 2.Princess Margaret HospitalTorontoCanada
  3. 3.Clinical Pharmacology Pfizer IncLa JollaUSA
  4. 4.Oncology Development Pfizer IncLa JollaUSA
  5. 5.Department of Hematology-OncologyUniversity of CincinnatiCincinnatiUSA

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