Originally published as JCO Early Release 10.1200/JCO.2007.13.5913 on February 19 2008

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Review of Phase II Trial Designs Used in Studies of Molecular Targeted Agents: Outcomes and Predictors of Success in Phase III

Robert H. El-Maraghi, Elizabeth A. Eisenhauer

From the Royal Victoria Hospital, Barrie; and National Cancer Institute of Canada Clinical Trials Group, Queen's University, Kingston, Ontario, Canada

Corresponding author: Elizabeth Eisenhauer, MD, FRCPC, National Cancer Institute of Canada Clinical Trials Group, Queen's University, 10 Stuart St, Kingston, Ontario, Canada K7L 3N6; e-mail: eeisenhauer{at}ctg.queensu.ca

Purpose: Because the appropriate design and end points for phase II evaluation of targeted anticancer agents are unclear, we undertook a review of recent reports of phase II trials of targeted agents to determine the types of designs used, the planned end points, the outcomes, and the relationship between trial outcomes and regulatory approval.

Methods: We retrieved reports of single-agent phase II trials in six solid tumors for 19 targeted drugs. For each, we abstracted data regarding planned design and actual results. Response rates were examined for any relationship to eventual success of the agents, as determined by US Food and Drug Administration approval for at least one indication.

Results: Eighty-nine trials were identified. Objective response was the primary or coprimary end point in the majority of trials (61 of 89 trials). Fourteen reports were of randomized studies generally evaluating different doses of agents, not as controlled experiments. Enrichment for target expression was uncommon. Objective responses were seen in 38 trials; in 19 trials, response rates were more than 10%, and in eight, they were more than 20%. Agents with high response rates tended to have high nonprogression rates; renal cell carcinoma was the exception to this. Higher overall response rates were predictive of regulatory approval in the tumor types reviewed (P = .005).

Conclusion: In practice, phase II design for targeted agents is similar to that for cytotoxics. Objective response seems to be a useful end point for screening new targeted agents because, in our review, its observation predicted for eventual success. Improvements in design are recommended, as is more frequent inclusion of biological questions as part of phase II trials.

published online ahead of print at www.jco.org on February 19, 2008.

The National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) is supported by a core grant from the National Cancer Institute of Canada with funds received from the Canadian Cancer Society. R.H.E.-M. was a Drug Development Fellow at NCIC CTG from 2005 to 2006 whose salary was supported by a Transdisciplinary Training Program Grant from the Canadian Institutes of Health Research as well as a Drug Development Fellowship grant from AstraZeneca.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA; and the National Cancer Research Institute Cancer Conference, October 8-11, 2006, Birmingham, United Kingdom.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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