A Multicenter Phase II Study of Sorafenib (BAY43-9006) in Non-GIST Sarcomas
A Multicenter Phase II Study of Sorafenib (BAY43-9006) in Non-GIST Sarcomas
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.
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.
Inclusion Criteria:
Histologically or cytologically confirmed sarcoma, including any of the following neoplastic subtypes:
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
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)
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
No prior sorafenib
No prior small molecule inhibitors of MAPK signaling intermediates
No concurrent therapeutic anticoagulation
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)