This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Eisenhauer, E. A. Articles by Humphrey, J. S. Search for Related Content PubMed PubMed Citation Articles by Eisenhauer, E. A. Articles by Humphrey, J. S. Social Bookmarking                            What's this?

Phase I Clinical Trial Design in Cancer Drug Development

From the National Cancer Institute of Canada Clinical Trials Group, Queen’s University, Kingston, Canada; Department of Hematology/Oncology, University of Pennsylvania, Philadelphia, PA; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD; and Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT.

Address reprint requests to Elizabeth Eisenhauer, MD, NCIC Clinical Trials Group, 82-84 Barrie St, Queen’s University, Kingston, Ontario, Canada K7L 3N6; email eeisenhauer{at}ctg.queensu.ca

ABSTRACT: The past decade has seen the publication of a number of new proposals for the design of phase I trials of anticancer agents. The purpose of these proposals has been to address ethical concerns about treating excessive numbers of patients at subtherapeutic doses of a new agent and to increase the overall efficiency of the process while enhancing the precision of the recommended phase II dose. In early 1998, a workshop of phase I investigators was held under the sponsorship of Bristol-Myers Squibb Pharmaceutical Research Institute (Wallingford, CT) to review the experience to date with novel phase I methodologies, with a particular focus on their efficiency and safety. This report summarizes the material presented. It was concluded that for phase I trials of antineoplastics (cytotoxics), which begin at 0.1 mouse-equivalent LD10 doses, evidence to date suggests that the historic approach of using a modified Fibonacci escalation and three patients per dose level is not necessary and is seldom used. One patient per dose level and more rapid escalation schemes, both empirically based and statistically based, are commonly used with apparent safety. There remain questions, however: Which of the dose escalation schemes is optimal? Are there alternatives to toxicity as a phase I end point, and will these end points be reliable in defining active doses? Answering these questions in a reasonable time frame will be important if new anticancer agents are not to suffer undue delays in phase I evaluation.

Report of a workshop on phase I trials design chaired by E.A.E. and P.J.O. and organized by Bristol-Myers Squibb, including summaries of presentations by E.A.E., J. Verweij, J. Collins, A. Rogatko, E. Rowinsky, M. Christian, P. Lorusso, H. Calvert, and M. Ratain, and as well the conclusions and final comments of the participants and coauthors.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				H.-T. Arkenau, J. Barriuso, D. Olmos, J. E. Ang, J. de Bono, I. Judson, and S. Kaye Prospective Validation of a Prognostic Score to Improve Patient Selection for Oncology Phase I Trials J. Clin. Oncol., June 1, 2009; 27(16): 2692 - 2696. [Abstract] [Full Text] [PDF]

				A.-R. Hanauske, M. Lahn, L. C. Musib, K. Weigang-Kohler, E. Yilmaz, T. Graefe, B. Kuenen, D. Thornton, P. McNealy, and G. Giaccone Phase Ib safety and pharmacokinetic evaluation of daily and twice daily oral enzastaurin in combination with pemetrexed in advanced/metastatic cancer Ann. Onc., June 1, 2009; (2009) mdp049v1. [Abstract] [Full Text] [PDF]

				C. Le Tourneau, J. J. Lee, and L. L. Siu Dose Escalation Methods in Phase I Cancer Clinical Trials J Natl Cancer Inst, May 20, 2009; 101(10): 708 - 720. [Abstract] [Full Text] [PDF]

				A. Iasonos, A. S Wilton, E. R Riedel, V. E Seshan, and D. R Spriggs A comprehensive comparison of the continual reassessment method to the standard 3 + 3 dose escalation scheme in Phase I dose-finding studies Clinical Trials, October 1, 2008; 5(5): 465 - 477. [Abstract] [PDF]

				S. Zohar, Qing Lian, V. Levy, K. Cheung, A. Ivanova, and S. Chevret Quality assessment of phase I dose-finding cancer trials: proposal of a checklist Clinical Trials, October 1, 2008; 5(5): 478 - 485. [Abstract] [PDF]

				J. S. Rader, C. F. Aylsworth, D. A. Juckett, D. G. Mutch, M. A. Powell, L. Lippmann, and N. V. Dimitrov Phase I Study and Preliminary Pharmacology of the Novel Innate Immune Modulator rBBX-01 in Gynecologic Cancers Clin. Cancer Res., May 15, 2008; 14(10): 3089 - 3097. [Abstract] [Full Text] [PDF]

				A. Dowlati, S. Manda, J. Gibbons, S. C. Remick, L. Patrick, and P. Fu Multi-Institutional Phase I Trials of Anticancer Agents J. Clin. Oncol., April 20, 2008; 26(12): 1926 - 1931. [Abstract] [Full Text] [PDF]

				M. Agulnik, A. M. Oza, G. R. Pond, and L. L. Siu Impact and Perceptions of Mandatory Tumor Biopsies for Correlative Studies in Clinical Trials of Novel Anticancer Agents J. Clin. Oncol., October 20, 2006; 24(30): 4801 - 4807. [Abstract] [Full Text] [PDF]

				D. Normolle and T. Lawrence Designing Dose-Escalation Trials With Late-Onset Toxicities Using the Time-to-Event Continual Reassessment Method J. Clin. Oncol., September 20, 2006; 24(27): 4426 - 4433. [Abstract] [Full Text] [PDF]

				J. A. Sparano, S. Moulder, A. Kazi, L. Vahdat, T. Li, C. Pellegrino, P. Munster, M. Malafa, D. Lee, S. Hoschander, et al. Targeted Inhibition of Farnesyltransferase in Locally Advanced Breast Cancer: A Phase I and II Trial of Tipifarnib Plus Dose-Dense Doxorubicin and Cyclophosphamide J. Clin. Oncol., July 1, 2006; 24(19): 3013 - 3018. [Abstract] [Full Text] [PDF]

				M. L. Hauck, S. M. LaRue, W. P. Petros, J. M. Poulson, D. Yu, I. Spasojevic, A. F. Pruitt, A. Klein, B. Case, D. E. Thrall, et al. Phase I Trial of Doxorubicin-Containing Low Temperature Sensitive Liposomes in Spontaneous Canine Tumors. Clin. Cancer Res., July 1, 2006; 12(13): 4004 - 4010. [Abstract] [Full Text] [PDF]

				D. D. Rosa, J. Harris, and G. C. Jayson The Best Guess Approach to Phase I Trial Design J. Clin. Oncol., January 1, 2006; 24(1): 206 - 208. [Full Text] [PDF]

				A. Rogatko, J. S. Babb, M. Tighiouart, F. R. Khuri, and G. Hudes New Paradigm in Dose-Finding Trials: Patient-Specific Dosing and Beyond Phase I Clin. Cancer Res., August 1, 2005; 11(15): 5342 - 5346. [Abstract] [Full Text] [PDF]

				B. B. Rothschild, N. M.P. King, F. M. Muggia, I. Sekine, T. Tamura, M. J. Miller, E. Horstmann, E. J. Emanuel, C. Grady, R. Kurzrock, et al. Phase 1 Clinical Trials in Oncology N. Engl. J. Med., June 9, 2005; 352(23): 2451 - 2453. [Full Text] [PDF]

				J. M. Yingling and S. Glatt Impact of PK/PD Evaluation of Targeted Therapies on Early Drug Discovery and Clinical Development Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 227 - 230. [Full Text] [PDF]

				E. Horstmann, M. S. McCabe, L. Grochow, S. Yamamoto, L. Rubinstein, T. Budd, D. Shoemaker, E. J. Emanuel, and C. Grady Risks and Benefits of Phase 1 Oncology Trials, 1991 through 2002 N. Engl. J. Med., March 3, 2005; 352(9): 895 - 904. [Abstract] [Full Text] [PDF]

				M. J. Ratain and S. G. Eckhardt Phase II Studies of Modern Drugs Directed Against New Targets: If You Are Fazed, Too, Then Resist RECIST J. Clin. Oncol., November 15, 2004; 22(22): 4442 - 4445. [Full Text] [PDF]

				E. X. Chen and I. F. Tannock Risks and Benefits of Phase 1 Clinical Trials Evaluating New Anticancer Agents: A Case for More Innovation JAMA, November 3, 2004; 292(17): 2150 - 2151. [Full Text] [PDF]

				A. Rogatko, J. S. Babb, H. Wang, M. J. Slifker, and G. R. Hudes Patient Characteristics Compete with Dose as Predictors of Acute Treatment Toxicity in Early Phase Clinical Trials Clin. Cancer Res., July 15, 2004; 10(14): 4645 - 4651. [Abstract] [Full Text] [PDF]

				W. R. Parulekar and E. A. Eisenhauer Phase I Trial Design for Solid Tumor Studies of Targeted, Non-Cytotoxic Agents: Theory and Practice J Natl Cancer Inst, July 7, 2004; 96(13): 990 - 997. [Abstract] [Full Text] [PDF]

				G. A. Omura Modified Fibonacci Search J. Clin. Oncol., August 15, 2003; 21(16): 3177 - 3177. [Full Text] [PDF]

				V. Grunwald and M. Hidalgo Developing Inhibitors of the Epidermal Growth Factor Receptor for Cancer Treatment J Natl Cancer Inst, June 18, 2003; 95(12): 851 - 867. [Abstract] [Full Text] [PDF]

				J. A. Deatrick, D. B. Angst, and C. Moore Parents' Views of their Children's Participation in Phase I Oncology Clinical Trials Journal of Pediatric Oncology Nursing, July 1, 2002; 19(4): 114 - 121. [Abstract] [PDF]

				S. Clive, D. J. Webb, A. MacLellan, A. Young, B. Byrne, L. Robson, J. F. Smyth, and D. I. Jodrell Forearm Blood Flow and Local Responses to Peptide Vasodilators: A Novel Pharmacodynamic Measure in the Phase I Trial of Antagonist G, a Neuropeptide Growth Factor Antagonist Clin. Cancer Res., October 1, 2001; 7(10): 3071 - 3078. [Abstract] [Full Text] [PDF]

				J. A. Sparano, U. Malik, L. Rajdev, C. Sarta, U. Hopkins, and A. C. Wolff Phase I Trial of Pegylated Liposomal Doxorubicin and Docetaxel in Advanced Breast Cancer J. Clin. Oncol., June 15, 2001; 19(12): 3117 - 3125. [Abstract] [Full Text] [PDF]

				S. G. Eckhardt, S. D. Baker, C. D. Britten, M. Hidalgo, L. Siu, L. A. Hammond, M. A. Villalona-Calero, S. Felton, R. Drengler, J. G. Kuhn, et al. Phase I and Pharmacokinetic Study of Irofulven, a Novel Mushroom-Derived Cytotoxin, Administered for Five Consecutive Days Every Four Weeks in Patients With Advanced Solid Malignancies J. Clin. Oncol., December 15, 2000; 18(24): 4086 - 4097. [Abstract] [Full Text] [PDF]

				K. A. Gelmon, J. Latreille, A. Tolcher, L. Genier, B. Fisher, D. Forand, S. D'Aloisio, L. Vernillet, L. Daigneault, A. Lebecq, et al. Phase I Dose-Finding Study of a New Taxane, RPR 109881A, Administered as a One-Hour Intravenous Infusion Days 1 and 8 to Patients With Advanced Solid Tumors J. Clin. Oncol., December 15, 2000; 18(24): 4098 - 4108. [Abstract] [Full Text] [PDF]

				J. M. Collins Innovations in Phase 1 Trial Design: Where Do We Go Next? Clin. Cancer Res., October 1, 2000; 6(10): 3801 - 3802. [Full Text]