Neoadjuvant and Adjuvant Imatinib Mesylate in Treating Patients With Primary or Recurrent Malignant Gastrointestinal Stromal Tumor

Study Overview
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Brief Summary
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Phase II trial to study the effectiveness of neoadjuvant and adjuvant imatinib mesylate in treating patients who are undergoing surgery for primary or recurrent malignant gastrointestinal stromal tumor. Imatinib mesylate may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Giving imatinib mesylate before and after surgery may shrink the tumor so it can be removed and may kill any tumor cells remaining after surgery.

Detailed Description
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OBJECTIVES: I. Determine the progression-free survival of patients with primary or recurrent potentially resectable malignant gastrointestinal stromal tumor treated with neoadjuvant and adjuvant imatinib mesylate. II. Determine the objective response rate of patients treated with this drug. III. Determine the safety of this drug in these patients. OUTLINE: Patients receive oral imatinib mesylate once daily. Treatment continues for 8 weeks in the absence of disease progression. Patients with disease progression are considered for immediate surgical resection. Otherwise, after 8 weeks, patients undergo surgical resection to debulk all gross tumor. Two to four weeks after surgery, patients receive oral imatinib mesylate once daily for 2 years. Patients are followed every 3 months for 2 years and then every 6 months for 3 years.

Official Title
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A Phase II Trial of Neoadjuvant/Adjuvant STI-571 (Gleevec NSC #716051) for Primary and Recurrent Operable Malignant GIST Expressing the KIT Receptor Tyrosine Kinase (CD117)

Conditions
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Gastrointestinal Stromal Tumor

Intervention / Treatment
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* Procedure: Conventional Surgery
* Drug: Imatinib Mesylate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed malignant gastrointestinal stromal tumor Potentially resectable primary disease Potentially resectable recurrent disease Local or intra-abdominal/pelvic metastatic disease Documented c-kit (CD117) expression by immunohistochemical analysis of either initial core specimen or, if recurrent disease, from original tumor block Primary disease must be visceral, intra-abdominal, or pelvic in origin At least 1 unidimensionally measurable lesion At least 5 cm for primary disease At least 2 cm for recurrent disease At least 1 viable core biopsy tumor specimen obtained within 8 weeks before registration Performance status - Zubrod 0-2 WBC at least 3,000/mm^3 Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Bilirubin no greater than 1.5 times upper limit of normal (ULN) ALT/AST no greater than 2.5 times ULN No uncontrolled chronic liver disease Creatinine no greater than 1.5 times ULN No uncontrolled chronic renal disease No New York Heart Association class III or IV cardiac disease Must be able to lie still in the PET scanner for approximately 1-2 hours No uncontrollable hyperglycemia No medical or psychological condition that would preclude study participation No severe or uncontrolled medical disease No active uncontrolled infection No known or suspected hypersensitivity to any component of the study drug Any prior malignancy is allowed provided patient remains disease free from that malignancy Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier contraception during and for 3 months after study participation At least 28 days since prior biologic therapy No concurrent filgrastim (G-CSF) or sargramostim (GM-CSF) At least 28 days since prior chemotherapy At least 28 days since prior radiotherapy See Disease Characteristics At least 28 days since prior investigational drugs At least 28 days since prior imatinib mesylate No concurrent therapeutic doses of warfarin Concurrent low-molecular weight heparin or mini-dose warfarin (1 mg per day) prophylaxis is allowed

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral imatinib mesylate once daily. Treatment continues for 8 weeks in the absence of disease progression. Patients with disease progression are considered for immediate surgical resection. Otherwise, after 8 weeks, patients undergo surgical resection to debulk all gross tumor. Two to four weeks after surgery, patients receive oral imatinib mesylate once daily for 2 years. | Procedure: Conventional Surgery<br>* Undergo surgical resection<br>Drug: Imatinib Mesylate<br>* Given orally<br>* Other names: STI571;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Disease Progression at 2 Years | Kaplan-Meier estimate of disease progression rate. Disease progression is determined by Response Evaluation Criteria in Solid Tumours criteria (RECIST). RECIST criteria is described here: http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf | From registration to two years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rates of Objective Response (Complete, Partial, and Stable) | The percentage of patients who achieved a complete, partial or stable response prior to surgery as assessed by Response Evaluation Criteria in Solid Tumours criteria (RECIST). RECIST criteria is described here: http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf. | Pretreatment and prior to surgery (at 4-10 weeks, based on surgery timing) | 
| Percentage of Patients With Major Toxicity (Toxicity Grade ≥ 3) | Highest grade toxicity per subject was counted. Toxicities were graded using Common Toxicity Criteria (CTC) v 2.0. Grade refers to the severity of the toxicity, using Grades 1 through 5 with unique clinical descriptions of severity for a given toxicity based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to toxicity. | Analysis occurs after all patients have been on study for at least 2 years. Measured from start of treatment to end of follow-up, to a maximum of 4.95 years. | 
| FDG-PET as Biological Marker of Metabolic Response(MR) During Imatinib Mesylate (IM) Treatment, in Patients With GIST Who Are naı¨ve to Tyrosine Kinase Inhibitor Therapy | evaluate FDG-PET as a non-invasive functional imaging tool to assess in situ tumor metabolism (as measured by the Standardized Uptake Values of FDG in the tumor) prior to and during the administration of IM. %change in SUVmax <1 indicate decreased tumor metabolism while values >1 indicated an increase in tumor metabolism. Metabolic response by 18F-FDG PET was determined in accordance with the criteria of the European Organization for Research and Treatment of Cancer EORTC), with increases or decreases of more than 25% in SUVmax defining progressive metabolic disease (PMD) and partial metabolic response (PMR), respectively, and new lesions defining PMD. | change from baseline to 1 week post therapy |