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Multi-Institutional Phase I Trials of Anticancer Agents

Afshin Dowlati, Sudhir Manda, Joseph Gibbons, Scot C. Remick, Lauren Patrick, Pingfu Fu

From the Division of Hematology/Oncology and the Department of Epidemiology and Biostatistics, Case Western Reserve University; University Hospitals Ireland Cancer Center; and the Case Comprehensive Cancer Center, Cleveland, OH

Corresponding author: Afshin Dowlati, MD, Division of Hematology/Oncology, University Hospitals Case Medical Center, 11100 Euclid Ave, Cleveland, OH 44106; e-mail: afshin.dowlati{at}case.edu

Purpose: Physicians involved in the conduct of phase I studies of novel anticancer agents have raised concerns about the emergence of multi-institutional phase I trials and about using the optimal biologic dose (OBD) as an alternative to the maximum-tolerated dose (MTD) as the primary end point in early drug development. We sought to determine the factors associated with multi-institutional phase I studies and OBD determination.

Patients and Methods: We reviewed all published phase I trials between January 1998 and June 2006 from two major clinical cancer journals. The following components from each trial were determined: number of participating sites, sponsor, nation where study was conducted, MTD or OBD established, number of patients accrued, mechanism of action of the studied agent, accrual time, and tumor type.

Results: We identified 463 trials. Fifty-six percent were performed in single institutions. Only 30% reported accrual time. The number of patients enrolled on single institution studies was significantly lower than on multi-institutional studies (P < .05), but there was no difference in accrual time. There was no association between the number of institutions and the sponsor or the mechanism of drug action. National Institutes of Health–sponsored trials enrolled fewer patients per trial than pharmaceutical-sponsored trials (P < .05). Although 99% of trials with cytotoxic agents determined an MTD, only 64% of trials with targeted agents did.

Conclusion: Multi-institutional phase I studies do not decrease the time to study completion and result in an increase in number of patients per trial. One third of trials with targeted agents failed to determine an MTD.

Supported by Grants No. 5K23 CA109348-01 and U01 CA62502 from the National Institutes of Health.

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

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				J. Verweij, F. Eskens, and M. de Jonge The Multi-Institutional Phase I Study: Disadvantages Without Advantages? J. Clin. Oncol., April 20, 2008; 26(12): 1915 - 1916. [Full Text] [PDF]