Sorafenib in Treating Patients With Soft Tissue Sarcomas (Extremity Sarcoma Closed to Entry as of 5/30/07)

Study Overview
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Brief Summary
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This phase II trial is studying how well sorafenib works in treating patients with soft tissue sarcoma. Sorafenib may stop the growth of soft tissue sarcoma by blocking blood flow to the tumor and blocking some of the enzymes needed for tumor cell growth

Detailed Description
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PRIMARY OBJECTIVES: I. To determine if the combined vascular endothelial growth factor receptor 2 (VEGF-R2)/platelet-derived growth factor receptor (PDGFR)-beta inhibitor BAY 43-9006/ sorafenib can decrease interstitial fluid pressure (IFP) in soft tissue sarcomas. II. To investigate the effects of BAY 43-9006/sorafenib on tumor blood flow, circulating endothelial cells, vascular density and pericyte coverage. III. To characterize the pharmacokinetics of BAY 43-9006/sorafenib in sarcoma patients. SECONDARY OBJECTIVES: I. To describe any preliminary evidence of anti-tumor activity. II. Assess whether there are any significant relationships between systemic drug exposure and drug-related toxicity or biological effect. OUTLINE: This is a multicenter study. Patients are assigned to one of two groups (group 1 closed to accrual as of 5/30/07). GROUP I (SARCOMAS OF THE EXTREMITY) (CLOSED TO ACCRUAL AS OF 5/30/07): Patients receive oral sorafenib twice daily on days 1-14. Patients undergo surgical resection of the tumor on approximately day 15. Once patients recover from surgery (and radiotherapy if indicated), patients who demonstrate a clinically and pathologically significant response (≥ 25% reduction in tumor size or ≥ 25% necrosis in the surgical specimen) may continue sorafenib as above for a maximum of 6 months in the absence of disease progression or unacceptable toxicity and at the discretion of the principal investigator. Biopsy tissue and blood samples are examined for biomarkers and interstitial fluid pressure (IFP) is measured at baseline and immediately before surgery. GROUP II (METASTATIC OR INOPERABLE SARCOMAS): Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days for 2 courses. Patients with responding or stable disease may continue sorafenib in the absence of disease progression or unacceptable toxicity. Biopsy tissue and blood samples are examined for biomarkers and IFP is measured at baseline and on days 28 and 56. In both groups, blood samples are drawn periodically for pharmacological studies. After completion of study therapy, patients are followed monthly until all study-related toxicities are resolved and then at the discretion of the investigator.

Official Title
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A Phase II Clinical and Correlative Study of BAY 43-9006 (Sorafenib) IND 69,896 in Sarcoma

Conditions
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Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Metastatic Osteosarcoma, Recurrent Adult Soft Tissue Sarcoma, Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Recurrent Osteosarcoma, Stage I Adult Soft Tissue Sarcoma, Stage II Adult Soft Tissue Sarcoma, Stage III Adult Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: sorafenib tosylate
* Procedure: therapeutic conventional surgery
* Other: laboratory biomarker analysis
* Other: pharmacological study
* Procedure: computed tomography
* Procedure: dynamic contrast-enhanced magnetic resonance imaging


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: There are two groups of patients eligible for this study; treatment group 1 consists of patients with extremity sarcomas other than potentially curable osteosarcoma or Ewing's sarcoma who are candidates for potentially curative surgery; treatment group 2 consists of patients with metastatic or inoperable sarcoma, for which there is no known curative or survival prolonging palliative therapy, or failure of these therapies; patients must have at least one site of measurable disease by radiologic imaging techniques; patients must have at least one palpable tumor mass with no overlying viscera which is amenable to biopsy; the tumor mass should be approximately 2 cm or greater in diameter; patients with smaller palpable tumors are eligible if participation is approved by the treating surgeon after discussion with the study chairperson As of 5/30/07, no subjects will accrue to Treatment Group I Life expectancy >= 2 months Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Pretreatment laboratory data, obtained within 14 days of study entry, must meet the following criteria: Absolute Neutrophil Count (ANC) >= 1,500/mm^3 Platelets >= 100,000/mm^3 Serum glutamic oxaloacetic transaminase (SGOT) =< 2.5-times the upper limit of normal (ULN) Serum glutamic-pyruvic transaminase (SGPT)=< 2.5-times ULN Total Bilirubin =< ULN Serum creatinine =< 1.5-times ULN >= 3 weeks since major surgery unrelated to study disease (sarcoma) >= 3 weeks since chemotherapy or radiation therapy (6 weeks for nitrosourea or mitomycin C chemotherapy) No prior treatment with sorafenib (BAY 43-9006) or specific inhibitors of mitogen-activated protein kinase (MAPK) pathways are permitted; a previously irradiated tumor site cannot be used for clinical or correlative measurements, although irradiation to sites other than a measurable site is permitted; there are no limitations on the extent or type of prior therapy received by the patient other than the time intervals indicated in the above and demonstrating complete recovery from any adverse effects associated by satisfying all relevant eligibility criteria Patients who are on warfarin anticoagulation are allowed to participate as long as they are converted to a low molecular weight heparin (e.g. lovenox) from study entry until at least day 56 Women of childbearing potential must not be pregnant or lactating; all women of childbearing potential (age < 50, last menstrual period [LMP] < 12 months ago) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L of beta-HCG) within 72 hr prior to receiving the study medication; BAY43-9006 has antiproliferative effects, which may be harmful to the developing fetus or nursing infant Fertile males and females must use adequate contraception Signed informed consent Exclusion Criteria: Ewing's sarcoma or osteosarcoma that is potentially curable with surgery, chemotherapy, and/or radiation therapy Active brain metastases including evidence of cerebral edema by CT scan or MRI, or progression from prior imaging study, any requirements for steroids, or enzyme-inducing anti-convulsant agents, or clinical symptoms of/from brain metastases; patients with treated and/or stable brain metastasis who are asymptomatic can be enrolled, if otherwise eligible Any uncontrolled serious medical or psychiatric illness; particular note is given to uncontrolled hypertension (discretion left to investigators) and significant proteinuria > 1 gm/24 hr (does not require quantitation in absence of clinical indication) Patients receiving other investigational agents Human immunodeficiency virus (HIV) patients receiving combination anti-retroviral therapy are excluded because of potential pharmacokinetic interactions

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (sarcomas of extremity, closed accrual as of 5/30/07)<br>Patients receive oral sorafenib twice daily on days 1-14. Patients undergo surgical resection of the tumor on approximately day 15. Once patients recover from surgery (and radiotherapy if indicated), patients who demonstrate a clinically and pathologically significant response (≥ 25% reduction in tumor size or ≥ 25% necrosis in the surgical specimen) may continue sorafenib as above for a maximum of 6 months in the absence of disease progression or unacceptable toxicity and at the discretion of the principal investigator. Biopsy tissue and blood samples are examined for biomarkers and interstitial fluid pressure (IFP) is measured at baseline and immediately before surgery. | Drug: sorafenib tosylate<br>* Given PO<br>* Other names: SFN;Procedure: therapeutic conventional surgery<br>* Undergo surgery<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Procedure: computed tomography<br>* Correlative studies<br>* Other names: tomography, computed;Procedure: dynamic contrast-enhanced magnetic resonance imaging<br>* Correlative studies<br>* Other names: DCE-MRI;|
| Experimental: Group II (metastatic or inoperable sarcomas)<br>Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days for 2 courses. Patients with responding or stable disease may continue sorafenib in the absence of disease progression or unacceptable toxicity. Biopsy tissue and blood samples are examined for biomarkers and IFP is measured at baseline and on days 28 and 56. | Drug: sorafenib tosylate<br>* Given PO<br>* Other names: SFN;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Procedure: computed tomography<br>* Correlative studies<br>* Other names: tomography, computed;Procedure: dynamic contrast-enhanced magnetic resonance imaging<br>* Correlative studies<br>* Other names: DCE-MRI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fludeoxyglucose (FDG) Uptake (Maximal Standardized Uptake Value, or SUVmax) | Paired comparison made using a Wilcoxon signed rank test with one-sided type I error of 5%. | Baseline to up to 1 month post-treatment | 
| Change in Interstitial Fluid Pressure (IFP) | Paired comparison made using a Wilcoxon signed rank test with one-sided type I error of 5%. | Baseline to up to 1 month post-treatment | 
| Change in White Blood Cell Count (WBC) | Paired comparison made using a Wilcoxon signed rank test with one-sided type I error of 5%. | Baseline to up to 1 month post-treatment | 
| Change in Pericyte Coverage of Endothelial Cells (Alpha-SMA) | Paired comparison made using a Wilcoxon signed rank test with one-sided type I error of 5%. | Baseline to up to 1 month post-treatment | 
| Clinical Benefit as Measured by 50% Reduction in IFP |  | Baseline to surgery | 
| Clinical Benefit, Measured by Any Reduction in Tumor Dimensions on CT Scan as Measured by RECIST Criteria |  | Up to 1 month | 
| Incidence of Adverse Events |  | Up to 1 month |