Sorafenib in Treating Patients With Malignant Gastrointestinal Stromal Tumor That Progressed During or After Previous Treatment With Imatinib Mesylate and Sunitinib Malate

• Toxicity [ Time Frame: Evaluated every 8 weeks ] [ Designated as safety issue: Yes ]
  All toxicities will be graded using the Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE v3), except for hypertension and rash. Minor changes from the CTCAE guidelines for hypertension and rash are based on observations in other trials and the frequency of monitoring in this protocol.
• Progression-free survival (time to disease progression or death) as assessed using standard Kaplan-Meier methods [ Time Frame: CT scans for disease reassessment will be obtained pre-therapy and every 8 weeks. In addition to a baseline scan, confirmatory scans will also be obtained 4 weeks following initial documentation of objective response. ] [ Designated as safety issue: No ]
  Progression-free survival will be documented according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria (e.g. there is a new lesion or there is 20% increase in unidimensional tumor size) from the start of treatment.
• Overall survival as assessed using standard Kaplan-Meier methods [ Time Frame: Unspecified ] [ Designated as safety issue: No ]
  Median overall survival and progression-free survival times will be estimated and confidence intervals generated using the method described in Brookmeyer and Crowley (1982).
• Mutational status of KIT and PDGFA [ Time Frame: Tumor specimens will be collected pre-therapy (at time of patient enrollment) for DNA extraction. If patient specimens are available following treatment with imatinib, these will be analyzed as well. ] [ Designated as safety issue: No ]
  Known sites of KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) mutations will be analyzed for correlation with response to drug. Mutational status will be correlated with outcomes by using Fisher's exact test to compare the frequency of responses in patients with and without specific mutations. These comparisons will have relatively low power and we will look for trends only. A Cox regression model will also be fit to determine whether there appears to be any association between mutational status and time to disease progression or death.

This phase II trial is studying how well sorafenib works in treating patients with malignant gastrointestinal stromal tumor that progressed during or after previous treatment with imatinib mesylate and sunitinib malate. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor

PRIMARY OBJECTIVES:

I. To determine the objective response rate of patients with imatinib and sunitinib-resistant malignant gastrointestinal stromal tumor who are treated with BAY 43-9006.

SECONDARY OBJECTIVES:

I. To determine the toxicity experienced by patients with imatinib and sunitinib -resistant malignant gastrointestinal stromal tumor who are treated with BAY 43-9006.

II. To determine progression-free survival and overall survival in patients with imatinib and sunitinib -resistant malignant gastrointestinal stromal tumor who are treated with BAY 43-9006.

TERTIARY OBJECTIVES:

I. To examine if mutational status of KIT and PDGFA in patients with imatinib- and sunitinib resistant malignant gastrointestinal stromal tumor correlate with response to BAY 43-9006.

OUTLINE: This is a multicenter study. Patients are stratified according to response to prior treatment with imatinib mesylate and sunitinib malate (imatinib mesylate- and sunitinib malate-responsive disease vs primary imatinib mesylate- and sunitinib malate-refractory disease).

Patients receive oral sorafenib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically.

Inclusion Criteria:

• Histologically confirmed gastrointestinal stromal tumor

  • Not amenable to curative surgery
• Kit-expressing tumor
• Disease progression (i.e., new lesion or 20% increase in unidimensional tumor size) on or after treatment with imatinib mesylate and sunitinib malate

• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion > 20 mm by conventional techniques OR > 10 mm by spiral CT scan

  • Only site of measurable disease must be outside of previously irradiated area
• No known brain metastases
• Performance status - ECOG 0-2
• More than 3 months
• Absolute neutrophil count > 1,500/mm^3
• Platelet count > 100,000/mm^3
• Bilirubin normal
• AST and ALT < 2.5 times upper limit of normal
• Creatinine ≤ 1.5 mg/dL
• Creatinine clearance > 60 mL/min
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• No uncontrolled hypertension
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other malignancy within the past 5 years except nonmelanoma skin cancer or carcinoma in situ of the cervix
• No history of allergic reaction attributed to compounds of similar chemical or biological composition to sorafenib
• No ongoing or active infection
• No psychiatric illness or social situation that would preclude study compliance
• No other uncontrolled illness
• No evidence of bowel perforation or obstruction
• No prior angiogenesis inhibitors
• No immunotherapy after the last dose of imatinib mesylate or sunitinib malate
• No chemotherapy or chemoembolization therapy after the last dose of imatinib mesylate or sunitinib malate
• See Disease Characteristics
• At least 4 weeks since prior radiotherapy and recovered
• At least 14 days since prior imatinib mesylate or sunitinib malate
• No prior sorafenib
• No prior inhibitors of MAPK-signaling intermediates
• No other investigational agent after the last dose of imatinib mesylate or sunitinib malate

• Concurrent anticoagulation therapy with warfarin allowed provided the following criteria are met:

  • On a therapeutic stable warfarin dose
  • INR ≤3
  • No active bleeding or pathologic condition that confers a high risk of bleeding
• No concurrent combination antiretroviral therapy for HIV-positive patients

• No concurrent administration of any of the following:

  • Enzyme-inducing antiepileptic drugs (e.g., carbamazepine, phenytoin, or phenobarbital)
  • Hypericum perforatum (St. John's wort)
  • Rifampin
• No other concurrent anticancer agents or therapies