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Journal of Clinical Oncology, Vol 26, No 21 (July 20), 2008: pp. 3654-3655 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.5315
In ReplyNational Cancer Institute of Canada Clinical Trials Group, Queen's University, Kingston, Ontario, Canada
Royal Victoria Hospital, Barrie, Ontario, Canada We thank Drs Leff and Andrews for their comments on our recent review on design and outcomes of single-agent phase II trials of targeted agents.1 We agree that a "road map" to successful drug development is something we would all like to see established, and many of the comments they raised are of great interest in that regard. However, it seems they have misunderstood, in part, our intent and conclusions. We did not state that agents with positive single-agent phase II data should proceed to phase III immediately: rather that the observation of responses in phase II was a useful marker for later positive results in phase III. This conclusion is useful, we think, given that the observation of objective response may be a helpful signal around which to make additional development plans for a targeted agent. This is in contrast to the views expressed some years ago, suggesting these agents were unlikely to produce tumor shrinkage because of their "noncytotoxic" mechanism of action.2-5 Although it is true that not all agents in our review that had a 0% response rate underwent phase III testing, many did. For example R115777, BB-2516, BMS-275291, and ISIS3521 were evaluated in randomized studies, and those trials have been negative.6-12 Thus, we believe single-agent data are likely to continue to be helpful in making decisions about whether a drug merits additional clinical testing. In most cases, that additional testing will not be to move the agent directly into phase III trials. Indeed, the development plan for any drug must be based not only on tumor types for which there is preliminary evidence of efficacy (as evidenced by single-agent activity), but also on several other factors, including the standard therapy effective in treating that tumor, the preclinical data supporting specific combinations, phase I combination data, and information from other trials of similar agents. With such data in hand, a rational development plan for that drug in a specific tumor may be developed. Randomized phase II combination data may play an important role in further development and may take the form of stand-alone studies or "seamless" randomized phase II-III trials, where the decision to proceed to the fully powered phase III trial is based on sufficient evidence of promise in the phase II portion to warrant the trial continuation. The dialogue on how best to develop targeted agents is an important one for all engaged in cancer drug development. Thus, we agree with the Drs Neff and Andrews that a review (or a prospective evaluation) focused on the development patterns of successful and unsuccessful agents after single-agent testing (or without single agent testing), would be extremely helpful in this regard. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. El-Maraghi RH, Eisenhauer EA: Review of phase II trial designs used in studies of molecular targeted agents: Outcomes and predictors of success in phase III. J Clin Oncol 26:1346-1354, 2008 2. Eisenhauer EA: Phase I and II trials of novel anti-cancer agents: Endpoints, efficacy and existentialism. Ann Oncol 10:1047-1052, 1998 3. Gelmon KA, Eisenhauer EA, Harris AL, et al: Anticancer agents targeting signaling molecules and cancer cell environment: Challenges for drug development? J Natl Cancer Inst 91:1281-1287, 1999 4. Korn EL, Arbuck SG, Pluda JM, et al: Clinical trial designs for cytostatic agents: Are new approaches needed? J Clin Oncol 19:265-272, 2001 5. Ratain MJ: Phase II oncology trials: Let's be positive. Clin Cancer Res 11:5661-5662, 2005 6. Van Cutsem E, Ven de Helde H, Karasek P, et al: Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 22:1430-1438, 2004 7. Sparano JA, Bernardo P, Stephenson P, et al: Randomized phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: Eastern Cooperative Oncology Group trial E2196. J Clin Oncol 22:4683-4690, 2004 8. Shepherd FA, Giaccone G, Seymour L, et al: Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: A trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of Cancer. J Clin Oncol 20:4434-4439, 2002 9. Bramhall SR, Schulz J, Nemunaitis J, et al: 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, 2002[CrossRef][Medline] 10. Leighl NB, Paz-Ares L, Douillard JY, et al: Randomized phase III study of matrix metalloproteinase inhibitor BMS-275291 in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: National Cancer Institute of Canada-Clinical Trials Group Study BR.18. J Clin Oncol 23:2831-2839, 2005 11. Paz-Ares L, Douillard JY, Koralewski P, et al: Phase III study of gemcitabine and cisplatin with or without aprinocarsen, a protein kinase C-alpha antisense oligonucleotide, in patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 24:1428-1434, 2006 12. Lynch TJ, Raju R, Lind M, et al: Randomized phase III trial of chemotherapy and antisense, oligonucleotide LY9000003 (ISIS 3521) in patients with advanced NSCLC: Initial report. Proc Am Soc Clin Oncol 22:623, 2003 (abstr 2504)
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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