Clinical Trials and Translational Applications in Cancer Therapy

Chapter

Despite the gains that had been made in increasing overall survival and extending disease-free survival rates, cancer is still one of the leading causes of death in the United States [1]. There remains an urgent need for the rapid development of new cancer therapeutics. Unfortunately, only about 5% of new compounds intended for use in cancer therapy are approved for clinical use [2]. The time and enormous costs involved in conducting clinical trials are special barriers to drug development [3, 4]. Careful thought regarding each phase of investigation is critical for the successful and efficient completion and interpretation of a clinical trial and prior to widespread clinical use of a new drug. This chapter focuses on clinical trials in oncology and translational applications. The global objectives of cancer clinical trials are to evaluate promising, new agents that may alleviate symptoms and/or cure the disease. As newer agents such as molecular targeted therapies are developed, questions remain as to whether current models of clinical trial design are sufficient. Nevertheless, classic design forms the basis of drug development in cancer therapy. Study objectives and endpoints are associated with specific study designs and determine the level of testing and the number of subjects required for each phase (Fig. 1) [5].

Keywords

Toxicity Tyrosine Paclitaxel Gefitinib Hypophosphatemia 

References

  1. 1.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin 2008; 58: 71–96.PubMedCrossRefGoogle Scholar
  2. 2.
    Kola I. The state of innovation in drug development. Clin Pharmacol Ther 2008; 83: 227–230.PubMedCrossRefGoogle Scholar
  3. 3.
    DiMasi J, Grabowski HG. Economics of new oncology drug development. J Clin Oncol 2007; 25: 209–216.PubMedCrossRefGoogle Scholar
  4. 4.
    Vickers AJ, Jang K, Sargent D, Lilja H, Kattan MW. Systematic review of statistical methods used in molecular marker studies in cancer. Cancer 2008; 112: 1862–1868.PubMedCrossRefGoogle Scholar
  5. 5.
    Nottage M, Siu LL. Principles of clinical trial design. J Clin Oncol 2002; 20: 42S–46S.PubMedCrossRefGoogle Scholar
  6. 6.
    FDA, Food and Drug Administration. 2008. http://www.fda.gov/oc/gcp/.
  7. 7.
    Murgo AJ, Kummar S, Rubinstein L, Gutierrez M, Collins J, Kinders R, Parchment RE, et al. Designing phase 0 cancer clinical trials. Clin Cancer Res 2008; 14: 3675–3682.PubMedCrossRefGoogle Scholar
  8. 8.
    Kummar S, Kinders R, Rubinstein L, Parchment RE, Murgo AJ, Collins J, Pickeral O, et al. Compressing drug development timelines in oncology using phase ‘0’ trials. Nat Rev Cancer 2007; 7: 131–139.PubMedCrossRefGoogle Scholar
  9. 9.
    Storer BE. Design and analysis of phase I clinical trials. Biometrics 1989; 45: 925–937.PubMedCrossRefGoogle Scholar
  10. 10.
    Gore L, Rothernberg ML, O'Bryant CL, Schultz MD, Sandler AB, Coffin D, McCoy C, et al. A phase I and pharmacokinetic study of the oral histone deacetylase inhibitor, MS-275, in patients with refractory solid tumors and lymphomas. Clin Cancer Res; 2008; 14: 4517–4525.PubMedCrossRefGoogle Scholar
  11. 11.
    Horstmann E, McCabe MS, Grochow L, Yamamoto S, Rubinstein L, Budd T, Shoemaker D, et al. Risks and benefits of phase 1 oncology trials, 1991 through 2002. N Engl J Med 2005; 352: 895–904.PubMedCrossRefGoogle Scholar
  12. 12.
    Rosa D, Harris DJ, Jayson GC. The best guess approach to phase I trial design. J Clin Oncol 2006; 24: 206–208.PubMedCrossRefGoogle Scholar
  13. 13.
    Calvert AH, Plummer R. The development of phase I cancer trial methodologies: the use of pharmacokinetic and pharmacodynamic end points sets the scene for phase 0 cancer clinical trials. Clin Cancer Res 2008; 14: 3664–3669.PubMedCrossRefGoogle Scholar
  14. 14.
    Booth CM, Calvert AH, Giaccone G, Lobbezoo MW, Seymour LK, Eisenhauer EA. Endpoints and other considerations in phase I studies of targeted anticancer therapy: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies (MDICT). Eur J Cancer 2008; 44: 19–24.PubMedCrossRefGoogle Scholar
  15. 15.
    Chen K, Shan M. Optimal and minimax three-stage designs for phase II oncology clinical trials. Contemp Clin Trial 2008; 29: 32–41.CrossRefGoogle Scholar
  16. 16.
    Parmar MK, Barthel FM, Sydes M, Langley R, Kaplan R, Eisenhauer E, Brady M, James N et al. Speeding up the evaluation of new agents in cancer. J Natl Cancer Inst 2008; 100: 1204–1214.PubMedCrossRefGoogle Scholar
  17. 17.
    Ratain MJ. Phase II oncology trials: let's be positive. Clin Cancer Res 2005; 11: 5661–5662.PubMedCrossRefGoogle Scholar
  18. 18.
    Sequist LV, Martins RG, Spigel D, Grunberg SM, Spira A, Janne PA, Joshi VA, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 2008; 26: 2442–2449.PubMedCrossRefGoogle Scholar
  19. 19.
    Armstrong DK, Bundy B, Wenzel L, Huang HG, Baergen R, Lele S, Copeland LJ, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006; 354: 34–43.PubMedCrossRefGoogle Scholar
  20. 20.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, et al. 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 Natl Cancer Inst 2000; 92: 205–216.PubMedCrossRefGoogle Scholar
  21. 21.
    Ratain MJ, Eckhardt SG. Phase II studies of modern drugs directed against new targets: if you are fazed, too, then resist RECIST. J Clin Oncol 2004; 22: 4442–4445.PubMedCrossRefGoogle Scholar
  22. 22.
    Ratain MJ, Karrison TG. Testing the wrong hypothesis in phase II oncology trials: there is a better alternative. Clin Cancer Res 2007; 13: 781–782.PubMedCrossRefGoogle Scholar
  23. 23.
    Abdoler E, Taylor H, Wendler D. The ethics of phase oncology trials. Clin Cancer Res 2008; 14: 3692–3697.PubMedCrossRefGoogle Scholar
  24. 24.
    Beecher HK. Ethics and clinical research. N Engl J Med 1966; 274: 1354–1360.PubMedCrossRefGoogle Scholar
  25. 25.
    Huang RS, Kistner EO, Bleibel WK, Shukla SJ, Dolan ME. Effect of population and gender on chemotherapeutic agent-induced cytotoxicity. Mol Cancer Ther 2007; 6: 31–36.PubMedCrossRefGoogle Scholar
  26. 26.
    Press OA, Zhang W, Gordon MA, Yang D, Lurje G, Iqbal S, El-Khoueiry A, et al. Gender-related survival differences associated with EGFR polymorphisms in metastatic colon cancer. Cancer Res 2008; 68: 3037–3042.PubMedCrossRefGoogle Scholar
  27. 27.
    Morris GJ, Naidu S, Topham AK, Guiles F, Xu Y, McCue P, Schwartz GF, et al. Differences in breast carcinoma characteristics in newly diagnosed African-American and Caucasian patients: a single-institution compilation compared with the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Cancer 2007; 110: 876–884.PubMedCrossRefGoogle Scholar
  28. 28.
    Khabele D. Racial and ethnic health disparities, women and cancer. The Medscape Journal 2005. http://cme.medscape.com/viewprogram/4412.
  29. 29.
    Colon-Otero G, Smallridge RC, Solberg LA Jr, Keith TD, Woodward TA, Willis FB, Dunn AN. Disparities in participation in cancer clinical trials in the United States : a symptom of a healthcare system in crisis. Cancer 2008; 112: 447–454.PubMedCrossRefGoogle Scholar
  30. 30.
    Ford JG, Howerton MW, Lai GY, Gary TL, Bolen S, Gibbons MC, Tilburt J, et al. Barriers to recruiting underrepresented populations to cancer clinical trials: a systematic review. Cancer 2008; 112: 228–242.PubMedCrossRefGoogle Scholar
  31. 31.
    Vargas RB, Ryan GW, Jackson A, Rodriguez R, Freeman HP. Characteristics of the original patient navigation programs to reduce disparities in the diagnosis and treatment of breast cancer. Cancer 2008; 113: 426–433.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Ob/Gyn DepartmentVanderbilt University Medical CenterNashvilleUSA
  2. 2.Department of SurgeryMeharry Medical CollegeNashvilleUSA

Personalised recommendations