Investigational New Drugs

, Volume 31, Issue 5, pp 1228–1235 | Cite as

An open-label study of the safety and tolerability of pazopanib in combination with FOLFOX6 or CapeOx in patients with colorectal cancer

  • Joanne Brady
  • Pippa Corrie
  • Ian Chau
  • Raghunadharao Digumarti
  • Laurel M. AdamsEmail author
  • Jeffrey Botbyl
  • Kevin H. Laubscher
  • Rachel S. Midgley
  • Mohandas Mallath


Background Although combining targeted agents with conventional, first-line cytotoxic therapy has improved survival outcomes in patients with advanced colorectal cancer, further improvements in outcomes and tolerability are needed. Methods This phase I study evaluated the feasibility of combining oral pazopanib, an agent that targets multiple proangiogenic factors, with FOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil) or CapeOx (oxaliplatin and capecitabine). This phase I study evaluated the optimally tolerated regimen of daily pazopanib (dose-escalated) plus standard FOLFOX6 or CapeOx in patients with advanced colorectal cancer. At the optimally tolerated regimen, each cohort was expanded to further evaluate safety and clinical response. Results The optimally tolerated regimens were pazopanib 800 mg plus FOLFOX6 and pazopanib 800 mg plus reduced CapeOx (capecitabine 850 mg/m2). The most commonly reported adverse events in the FOLFOX6 cohorts included decreased appetite, neutropenia, diarrhea, peripheral neuropathy, and vomiting. Similarly, the most commonly reported adverse events in the CapeOx cohorts included fatigue, vomiting, and decreased appetite. The overall response rate was 40 % (8/20 patients) in the pazopanib plus FOLFOX6 cohorts and 38 % (8/21 patients) in the pazopanib plus CapeOx cohorts. Conclusion Pazopanib combined with FOLFOX6 or reduced CapeOx was adequately tolerated in this patient population.


CapeOx Colorectal cancer Dose escalation FOLFOX6 Pazopanib 



The authors thank Jerome F. Sah, PhD, of ProEd Communications, Beachwood, Ohio, for his medical editorial assistance with this manuscript. The authors also would like to acknowledge Theresia Peckham of Trio Clinical Research, LLC, Raleigh, North Carolina, for her contributions to the conduct of the study and to the initial draft of the manuscript, and Medical Monitors Jo Lager, MD (formerly of GlaxoSmithKline), and Derry Ridgeway, MD, of SRA International, Merced, California.


This study was sponsored by GlaxoSmithKline Pharmaceuticals, Philadelphia, Pennsylvania. Financial support for medical editorial assistance was also provided by GlaxoSmithKline. Dr. Midgley acknowledges research support from the United Kingdom Department of Health (DH) Higher Education Funding Council for England (HEFCE) and Oxford National Institute for Health Research (NIHR) Biomedical Research Centre. Dr. Brady acknowledges research support from Cancer Research UK and the Experimental Cancer Medicine Centre. Dr. Chau would like to acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre.

Conflict of Interest Disclosure

J. Brady, P. Corrie, R. Digumarti, and R.S. Midgley report no potential conflict of interest. I. Chau has received honoraria from Roche and has served on advisory boards for Roche and Merck Serono. M. Mallath reports current research sponsored by GlaxoSmithKline Pharmaceuticals and participation in speakers bureaus for Roche and Dr. Reddy’s Laboratories. L. Adams and K. Laubscher are currently employed by GlaxoSmithKline and hold company stock positions. J. Botbyl is a paid statistical consultant for GlaxoSmithKline.

Ethical Standards

This study was conducted in compliance with the current laws of the countries (United Kingdom and India) in which it was conducted.


  1. 1.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917. doi: CrossRefGoogle Scholar
  2. 2.
    de Gramont A, Figer A, Seymour M et al (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938–2947CrossRefGoogle Scholar
  3. 3.
    Goldberg RM, Sargent DJ, Morton RF et al (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23–30CrossRefGoogle Scholar
  4. 4.
    Tournigand C, Andre T, Achille E et al (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22:229–237CrossRefGoogle Scholar
  5. 5.
    Diaz-Rubio E, Tabernero J, Gomez-Espana A et al (2007) Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol 25:4224–4230CrossRefGoogle Scholar
  6. 6.
    Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342CrossRefGoogle Scholar
  7. 7.
    Giantonio BJ, Catalano PJ, Meropol NJ et al (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539–1544CrossRefGoogle Scholar
  8. 8.
    Engstrom PF, Arnoletti JP, Benson AB 3rd et al (2009) NCCN clinical practice guidelines in oncology: colon cancer. J Natl Compr Canc Netw 7:778–831CrossRefGoogle Scholar
  9. 9.
    Van Cutsem EJ, Oliveira J (2008) Colon cancer: ESMO clinical recommendations for diagnosis, adjuvant treatment and follow-up. Ann Oncol 19(Suppl 2):29–30. doi: Google Scholar
  10. 10.
    Saltz LB, Clarke S, Diaz-Rubio E et al (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26:2013–2019. doi: CrossRefGoogle Scholar
  11. 11.
    Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62CrossRefGoogle Scholar
  12. 12.
    Sonpavde G, Hutson TE (2007) Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep 9:115–119CrossRefGoogle Scholar
  13. 13.
    Kumar R, Knick VB, Rudolph SK et al (2007) Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 6:2012–2021CrossRefGoogle Scholar
  14. 14.
    Schmoll HJ, Cartwright T, Tabernero J et al (2007) Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol 25:102–109CrossRefGoogle Scholar
  15. 15.
    National Cancer Institute Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Accessed November 2, 2012
  16. 16.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216CrossRefGoogle Scholar
  17. 17.
    Haller DG, Cassidy J, Tabernero J et al. (2010) Efficacy findings from a randomized phase III trial of capecitabine plus oxaliplatin versus bolus 5-FU/LV for stage III colon cancer (NO16968): Impact of age on disease-free survival (DFS). J Clin Oncol 28:abstr 3521CrossRefGoogle Scholar
  18. 18.
    Cassidy J, Clarke S, Diaz-Rubio E et al (2008) Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 26:2006–2012. doi: CrossRefGoogle Scholar
  19. 19.
    Rothenberg ML, Navarro M, Butts C et al. (2007) Phase III trial of capecitabine + oxaliplatin (XELOX) vs. 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (FOLFOX4) as 2nd-line treatment for patients with metastatic colorectal cancer (MCRC). J Clin Oncol 25:abstr 4031CrossRefGoogle Scholar
  20. 20.
    Adams RA, Meade AM, Madi A et al (2009) Toxicity associated with combination oxaliplatin plus fluoropyrimidine with or without cetuximab in the MRC COIN trial experience. Br J Cancer 100:251–258CrossRefGoogle Scholar
  21. 21.
    Hochster HS, Hart LL, Ramanathan RK et al (2008) Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol 26:3523–3529. doi: CrossRefGoogle Scholar
  22. 22.
    Baird R, Biondo A, Chhaya V et al (2011) Toxicity associated with capecitabine plus oxaliplatin in colorectal cancer before and after an institutional policy of capecitabine dose reduction. Br J Cancer 104:43–50. doi: CrossRefGoogle Scholar
  23. 23.
    Haller DG, Cassidy J, Clarke SJ et al (2008) Potential regional differences for the tolerability profiles of fluoropyrimidines. J Clin Oncol 26:2118–2123. doi: CrossRefGoogle Scholar
  24. 24.
    Hutson TE, Davis ID, Machiels JP et al (2010) Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol 28:475–480. doi: CrossRefGoogle Scholar
  25. 25.
    Sternberg CN, Davis ID, Mardiak J et al (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28:1061–1068. doi: CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Joanne Brady
    • 1
    • 8
  • Pippa Corrie
    • 2
  • Ian Chau
    • 3
  • Raghunadharao Digumarti
    • 4
  • Laurel M. Adams
    • 5
    Email author
  • Jeffrey Botbyl
    • 5
  • Kevin H. Laubscher
    • 5
  • Rachel S. Midgley
    • 6
  • Mohandas Mallath
    • 7
  1. 1.Department of Medical OncologyUniversity of Oxford Churchill HospitalOxfordUK
  2. 2.Cambridge University HospitalsCambridgeUK
  3. 3.Royal Marsden HospitalSuttonUK
  4. 4.Nizam’s Institute of Medical SciencesHyderabadIndia
  5. 5.GlaxoSmithKlineResearch Triangle ParkUSA
  6. 6.Department of Clinical PharmacologyUniversity of Oxford Churchill HospitalOxfordUK
  7. 7.Tata Memorial HospitalMumbaiIndia
  8. 8.Dorset Cancer CentrePoole Hospital Foundation TrustPooleUK

Personalised recommendations