Sorafenib in Treating Patients With Metastatic, Locally Advanced, or Recurrent Sarcoma

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 metastatic, locally advanced, or recurrent sarcoma. 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.

Detailed Description
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PRIMARY OBJECTIVES: I. The primary endpoint is the response rate (CR+PR) for each stratum of sarcoma patients treated with sorafenib as defined by RECIST. SECONDARY OBJECTIVES: I. Progression-free survival (defined as CR + PR + SD, assessed at 3 months or 6 months). II. Overall survival. III. Pharmacokinetics of sorafenib in this patient population (all sites will participate). IV. Frequency of B-raf mutations in the patients' sarcomas treated as part of this study and correlation with response or resistance to sorafenib (all sites will participate). V. Ras-raf kinase pathway activation in pre-treatment existing tumor specimens (paraffin section immunohistochemistry; all sites will participate). VI. At MSKCC only: Pre and post treatment specimen changes in downstream events of ras signaling, specifically inhibition of ERK phosphorylation. Only patients with angiosarcoma and MPNST will undergo biopsy (up to 10 patients). VII. At MSKCC only: Circulating Endothelial Cells (CECs), VE-cadherin levels, and soluble protein levels (VEGF, bFGF, endostatin) as a measures of angiogenesis before and after starting sorafenib therapy. OUTLINE: This is an open-label, non-randomized, multicenter study. Patients are stratified according to sarcoma histology (angiosarcoma vs malignant peripheral nerve sheath tumor vs leiomyosarcoma [closed to accrual as of 11/29/06] vs high-grade undifferentiated pleomorphic sarcoma [i.e., malignant fibrous histiocytoma (including myxofibrosarcoma)(closed to accrual as of 11/29/06)] vs synovial sarcoma (closed to accrual as of 11/29/06) vs all other types of sarcoma). 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, patients are followed at 4 weeks.

Official Title
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A Multicenter Phase II Study of Sorafenib (BAY43-9006) in Non-GIST Sarcomas

Conditions
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Adult Angiosarcoma, Adult Epithelioid Sarcoma, Adult Leiomyosarcoma, Adult Malignant Fibrous Histiocytoma, Adult Neurofibrosarcoma, Adult Synovial Sarcoma, Ovarian Sarcoma, Recurrent Adult Soft Tissue Sarcoma, Recurrent Uterine Sarcoma, Stage III Adult Soft Tissue Sarcoma, Stage III Uterine Sarcoma, Stage IV Adult Soft Tissue Sarcoma, Stage IV Uterine Sarcoma, Uterine Carcinosarcoma, Uterine Leiomyosarcoma

Intervention / Treatment
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* Drug: sorafenib tosylate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed sarcoma, including any of the following neoplastic subtypes: Giant hemangioma Angiosarcoma (including epithelioid hemangioendothelioma) Malignant peripheral nerve sheath tumor Leiomyosarcoma (closed to accrual as of 11/29/06) High-grade undifferentiated pleomorphic sarcoma (i.e., malignant fibrous histiocytoma [including myxofibrosarcoma]) (closed to accrual as of 11/29/06) Synovial sarcoma (closed to accrual as of 11/29/06) Carcinosarcoma (closed to accrual as of 11/29/06) Metastatic, locally advanced, or locally recurrent disease Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan Lesions in a previously irradiated area may be considered measurable provided there is evidence of subsequent disease progression that cannot be attributed to necrosis or bleeding No gastrointestinal stromal tumor No known brain metastases Performance status - ECOG 0-2 Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 No evidence of bleeding diathesis Bilirubin ≤ 1.5 mg/dL INR ≤ 1.5 AST and ALT ≤ 2.5 times upper limit of normal Creatinine ≤ 1.5 mg/dL No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia No uncontrolled hypertension No history of allergic reaction to compounds of similar chemical or biologic composition to sorafenib No known HIV positivity No active or ongoing infection Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No psychiatric illness or social situation that would preclude study compliance No swallowing dysfunction that would preclude the swallowing of tablets Other malignancies allowed provided sarcoma is the primary disease requiring treatment No other uncontrolled illness No more than 1 prior chemotherapy regimen for recurrent or metastatic disease (≤ 3 regimens for angiosarcoma or malignant peripheral nerve sheath tumor) Adjuvant chemotherapy completed > 1 year prior to study entry is not considered a line of prior treatment More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) At least 3 weeks since prior radiotherapy Recovered from prior antitumor therapy Alopecia allowed No prior sorafenib No prior small molecule inhibitors of MAPK signaling intermediates No concurrent therapeutic anticoagulation Prophylactic anticoagulation (i.e., low-dose warfarin) of venous or arterial devices allowed provided requirements for PT, INR, or PTT requirements are met No other concurrent investigational agents No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, or phenobarbital) No concurrent rifampin or Hypericum perforatum (St. John's wort)

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 sorafenib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: sorafenib tosylate<br>* Given orally<br>* Other names: SFN;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST | A 5% response rate is considered not promising, a 20% response rate is considered promising. For each stratum, the response rate will be estimated and a confidence interval will be constructed. | Up to 4 weeks |