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Successful Implementation of the Randomized Discontinuation Trial Design: An Application to the Study of the Putative Antiangiogenic Agent Carboxyaminoimidazole in Renal Cell Carcinoma—CALGB 69901

From the University of ChicagoMedical Center, Chicago, IL; Cancer and Leukemia Group B Statistical Center, Durham; Southeast Cancer Control Consortium Inc, CCOP, Goldsboro, NC; University of California at San Francisco, San Francisco, CA; University of Iowa, Iowa City, IA

Address reprint requests to Walter M. Stadler, MD, Associate Professor of Medicine, University of Chicago, Section of Hematology/Oncology, 5841 S Maryland Ave, MC-2115, Chicago, IL 60637; e-mail: wstadler{at}medicine.bsd.uchicago.edu

PURPOSE: To assess the disease-stabilizing activity of carboxyaminoimidazole (CAI) in patients with metastatic renal cell cancer (RCC) using a randomized discontinuation trial (RDT) design.

PATIENTS AND METHODS: Recruited patients had a performance status of 0 to 2, minimal neuropathy or cerebellar dysfunction, measurable disease, and normal organ function. Treatment with 250 mg/d CAI was initiated in all patients and continued until disease progression in those with an objective response. Protocol treatment was discontinued for unacceptable toxicity or progressive disease; patients with stable disease at the 16-week evaluation point were randomly assigned in a double-blind manner to continued CAI or placebo. The primary end point was the stable disease rate in the randomized groups.

RESULTS: A total of 368 patients were accrued and received therapy. Ninety percent had a performance status of 0 or 1, 80% underwent a prior nephrectomy, and 41% had received no prior systemic therapy. Serious or life-threatening toxicity was experienced by 34%, with asthenia (15%) and neuropsychiatric difficulties (7%) being most common. At the randomization point, 51% of patients had progressed, 30% withdrew, 1% experienced a partial response, and 17% had stable disease and were randomly assigned. A Bayesian futility analysis utilizing the first 49 randomly assigned patients suggested that the probability of demonstrating a higher stable disease rate in the experimental group was less than 9% even under the most optimistic a priori assumptions, and further trial accrual was halted.

CONCLUSION: CAI is inactive in RCC. The RDT design should be further explored for evaluating activity of putative disease stabilizing agents.

Supported by CA41287, supported by CA33601, supported by CA60138, supported by CA47642, supported by CA45808. The research for CALGB 69901 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (Richard L. Schilsky, MD, Chairman). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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