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

Phase 2

Completed

Conditions: Adult Angiosarcoma
Adult Neurofibrosarcoma
Recurrent Adult Soft Tissue Sarcoma
Recurrent Uterine Sarcoma
Stage III Adult Soft Tissue Sarcoma
Stage III Uterine Sarcoma
Adult Epithelioid Sarcoma
Adult Leiomyosarcoma
Stage IV Adult Soft Tissue Sarcoma
Stage IV Uterine Sarcoma

Interventions: Drug: sorafenib tosylate

Registration Number: NCT00245102

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 147

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)

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm I	sorafenib tosylate	Patients receive oral sorafenib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST	Up to 4 weeks	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.

Secondary Outcome Measures