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Phase III Randomized, Intergroup Trial Assessing Imatinib Mesylate At Two Dose Levels in Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumors Expressing the Kit Receptor Tyrosine Kinase: S0033

Charles D. Blanke, Cathryn Rankin, George D. Demetri, Christopher W. Ryan, Margaret von Mehren, Robert S. Benjamin, A. Kevin Raymond, Vivien H.C. Bramwell, Laurence H. Baker, Robert G. Maki, Michael Tanaka, J. Randolph Hecht, Michael C. Heinrich, Christopher D.M. Fletcher, John J. Crowley, Ernest C. Borden

From the Oregon Health & Science University Cancer Institute, Portland, OR; Southwest Oncology Group Statistical Center, Seattle, WA; Fox Chase Cancer Center, Philadephia, PA; Dana-Farber/Harvard Cancer Center, Boston, MA; The University of Texas M.D. Anderson Cancer Center, Houston, TX; London Regional Cancer Center, Calgary, Alberta, Canada; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; Memorial Hospital, New York, NY; University of California, Davis, Sacramento; University of California, Los Angeles, Los Angeles, CA; and the Cleveland Clinic Foundation, Cleveland, OH

Corresponding author: Charles D. Blanke, MD, Oregon Health & Science University Cancer Institute, 3181 SW Sam Jackson Park Rd, L-586, Portland, OR 97239; e-mail: blankec{at}ohsu.edu

Purpose To assess potential differences in progression-free or overall survival when imatinib mesylate is administered to patients with incurable gastrointestinal stromal tumors (GIST) at a standard dose (400 mg daily) versus a high dose (400 mg twice daily).

Patients and Methods Patients with metastatic or surgically unresectable GIST were eligible for this phase III open-label clinical trial. At registration, patients were randomly assigned to either standard or high-dose imatinib, with close interval follow-up. If objective progression occurred by Response Evaluation Criteria in Solid Tumors, patients on the standard-dose arm could reregister to the trial and receive the high-dose imatinib regimen.

Results Seven hundred forty-six patients with advanced GIST from 148 centers across the United States and Canada were enrolled onto this trial in 9 months. With a median follow-up of 4.5 years, median progression-free survival was 18 months for patients on the standard-dose arm, and 20 months for those receiving high-dose imatinib. Median overall survival was 55 and 51 months, respectively. There were no statistically significant differences in objective response rates, progression-free survival, or overall survival. After progression on standard-dose imatinib, 33% of patients who crossed over to the high-dose imatinib regimen achieved either an objective response or stable disease. There were more grade 3, 4, and 5 toxicities noted on the high-dose imatinib arm.

Conclusion This trial confirms the effectiveness of imatinib as primary systemic therapy for patients with incurable GIST but did not show any advantage to higher dose treatment. It appears reasonable to initiate therapy with 400 mg daily and to consider dose escalation on progression of disease.

Supported in part by the following PHS Cooperative Agreement Grants No. CA38926, CA32102, CA27057, CA68183, CA46441, CA04919, CA20319, CA45377, CA35192, CA14028, CA35261, CA63844, CA63850, CA35119, CA76447, CA13612, CA46282, CA58861, CA35178, CA46113, CA42777, CA35090, CA45560, CA45807, CA35176, CA12644, 58348, CA46368, CA16385, CA37981, CA58416, CA63845, CA58882, CA45450, CA35262, CA86780, CA35281, CA58666, CA22433, CA27525, CA21115, CA31946, CA31946, CA33601, CA31946, CA71323, CA47559, CA41287, CA32291, CA04326, CA47577, CA35091, CA35113, CA11028, CA12449, CA16450, CA114558-02, CA04457, CA77651, CA77658, CA08025, CA02599, CA11789, CA60138, CA77440, CA03927, NCI contracts U01-CA70172-01 and N01-CM-17003, awarded by the National Cancer Institute, Department of Health and Human Services (Bethesda, MD), and in part by Novartis.

Presented in part at the 40th and 41st Annual Meetings of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004, and Orlando, FL, May 13-15, 2005.

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

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