RATIONALE: STI571 may interfere with the growth of tumor cells and may be an effective treatment for cancer. It is not yet known which dose of STI571 is more effective in treating gastrointestinal stromal tumors.

PURPOSE: Randomized phase III trial to compare the effectiveness of two different doses of STI571 in treating patients who have metastatic or unresectable gastrointestinal stromal tumor.

OBJECTIVES: I. Compare the overall and progression-free survival of patients with CD117- expressing metastatic or unresectable gastrointestinal stromal tumor treated with two different doses of imatinib mesylate. II. Compare the confirmed, unconfirmed, complete, and partial response rates in patients treated with these regimens. III. Compare the toxic effects of these regimens in these patients.

OUTLINE: This is a randomized study. Patients are stratified according to Zubrod performance status (0-2 vs 3) and measurable disease (yes vs no). Patients are randomized to one of two treatment arms. Arm I: Patients receive oral imatinib mesylate once daily. Arm II: Patients receive oral imatinib mesylate twice daily. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients in arm I with progressive disease may cross over to arm II and receive treatment in the absence of further disease progression. Patients are followed every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter.

PROJECTED ACCRUAL: A total of 600 patients will be accrued for this study within 24 months.

• Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, Raymond AK, Bramwell VH, Baker LH, Maki RG, Tanaka M, Hecht JR, Heinrich MC, Fletcher CD, Crowley JJ, Borden EC. 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. J Clin Oncol. 2008 Feb 1;26(4):626-32.
• Heinrich MC, Owzar K, Corless CL, Hollis D, Borden EC, Fletcher CD, Ryan CW, von Mehren M, Blanke CD, Rankin C, Benjamin RS, Bramwell VH, Demetri GD, Bertagnolli MM, Fletcher JA. Correlation of Kinase Genotype and Clinical Outcome in the North American Intergroup Phase III Trial of Imatinib Mesylate for Treatment of Advanced Gastrointestinal Stromal Tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol. 2008 Oct 27; [Epub ahead of print]
• Choi H, Charnsangavej C, de Castro Faria S, Tamm EP, Benjamin RS, Johnson MM, Macapinlac HA, Podoloff DA. CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate treatment: a quantitative analysis correlated with FDG PET findings. AJR Am J Roentgenol. 2004 Dec;183(6):1619-28.
• Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, Issels R, van Oosterom A, Hogendoorn PC, Van Glabbeke M, Bertulli R, Judson I. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004 Sep 25-Oct 1;364(9440):1127-34.

DISEASE CHARACTERISTICS: Histologically confirmed gastrointestinal stromal tumor Distantly metastatic or unresectable disease Visceral or intra-abdominal primary disease Immunohistochemical documentation of CD117 expression No known brain metastasis

PATIENT CHARACTERISTICS: Age: 15 and over Performance status: Zubrod 0-3 Life expectancy: Not specified Hematopoietic: Absolute neutrophil count at least 1,000/mm3 Platelet count at least 100,000/mm3 Hemoglobin at least 9 g/dL (transfusion allowed) Hepatic: Bilirubin no greater than 1.5 times upper limit of normal (ULN) SGOT or SGPT no greater than 2.5 times ULN (5 times ULN if liver metastases present) No uncontrolled chronic liver disease Renal: Creatinine no greater than 1.5 times ULN No uncontrolled chronic renal disease Cardiovascular: No New York Heart Association class III or IV heart disease No congestive heart failure No myocardial infarction within the past 2 months Other: Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier contraception during and for up to 3 months after study participation No other severe and/or uncontrolled medical disease No uncontrolled diabetes No active uncontrolled infection (e.g., HIV) No medical or psychological condition that would preclude study participation No other prior malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or stage I or II cancer in complete remission

PRIOR CONCURRENT THERAPY: Biologic therapy: At least 28 days since prior biologic therapy and recovered No concurrent anti-cancer biologic therapy Chemotherapy: At least 28 days since prior chemotherapy and recovered No concurrent chemotherapy Endocrine therapy: Recovered from prior endocrine therapy Radiotherapy: Recovered from prior radiotherapy No concurrent radiotherapy Surgery: At least 14 days since prior major surgery and recovered Other: At least 28 days since prior investigational drug and recovered No concurrent therapeutic anticoagulation with warfarin Concurrent mini-dose oral warfarin (1 mg/day) allowed as prophylaxis for central venous catheter thrombosis Concurrent therapeutic anticoagulation with low-molecular weight heparin (e.g., enoxaparin) or other agents allowed No other concurrent investigational drugs

• National Cancer Institute (NCI)
• Southwest Oncology Group
• Eastern Cooperative Oncology Group
• NCIC Clinical Trials Group