Chemotherapy, SU5416, Radiation Therapy, and Surgery in Treating Patients With Soft Tissue Sarcoma

OBJECTIVES:

• Determine the maximum tolerated dose of SU5416 when administered with neoadjuvant chemotherapy and radiotherapy and adjuvant chemotherapy in patients with high-grade stage IIC-III soft tissue sarcoma.
• Determine the disease-free survival, local control, and overall survival in patients treated with this regimen.
• Determine histological response in patients treated with this regimen.
• Determine the toxicity of this regimen in these patients.
• Determine the quantitative antiangiogenic effects of SU5416 in patients treated with this regimen.

OUTLINE: This is a dose-escalation study of SU5416.

Patients receive neoadjuvant chemotherapy comprising doxorubicin, ifosfamide, and dacarbazine IV continuously on days 1-3, 22-24, and 43-45. Patients also receive filgrastim (G-CSF) subcutaneously once daily beginning on day 5 and continuing until blood counts recover. Patients undergo 2 courses of radiotherapy, given once daily for 11 doses per course over days 7-20 and 28-41. Patients also receive SU5416 IV over 1 hour twice weekly beginning on day 1 and continuing until 2 days before surgery. Patients undergo surgical resection on day 80. Patients then receive adjuvant chemotherapy comprising doxorubicin, ifosfamide, and dacarbazine IV continuously on days 101-103, 122-124, and 143-145. Patients also receive SU5416 IV over 1 hour twice weekly beginning on day 101 and continuing until the end of adjuvant chemotherapy. Patients with positive surgical margins receive additional radiotherapy beginning 2 weeks after resection for a total of 8 doses.

Cohorts of 3-6 patients receive escalating doses of SU5416 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: Approximately 68-80 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed stage IIC-III primary or locally recurrent soft tissue sarcoma

• Grade 2 or 3 on grade 1-3 scale OR
• Grade 3 or 4 on grade 3-4 scale
• Tumor size at least 8 cm in diameter
• Tumor located on upper extremities (including shoulder), lower extremities (including hip), or on body wall
• No rhabdomyosarcoma, extraosseous Ewing's sarcoma, primitive neuroectodermal tumors, osteosarcoma or chondrosarcoma, Kaposi's sarcoma or angiosarcoma of the scalp or face, or any sarcoma of the head and neck
• No evidence of lung metastases
• Maximum of 4 chest lesion no greater than 3 mm in diameter each on preoperative chest CT scans

• Lesions no greater than 1 cm in diameter allowed if stable for at least 1 year and fit criteria for granulomas

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Zubrod 0-1

Life expectancy:

• At least 2 years

Hematopoietic:

• WBC at least 4,000/mm^3 OR
• Absolute neutrophil count at least 1,800/mm^3
• Platelet count at least 150,000/mm^3
• No prior bleeding or clotting diathesis

Hepatic:

• Bilirubin no greater than 1.5 mg/dL
• AST and ALT no greater than 1.5 times upper limit of normal
• PT and PTT less than 1.25 times normal (not on coumadin)

Renal:

• Creatinine no greater than 1.5 mg/dL OR
• Creatinine clearance greater than 60 mL/min

Cardiovascular:

• LVEF greater than 50%
• History of atherosclerotic coronary artery disease (CAD) requiring bypass surgery allowed provided surgery occurred at least 1 year prior to study entry
• No uncompensated CAD on electrocardiogram or physical examination
• No myocardial infarction or severe or unstable angina within the past 6 months
• No New York Heart Association class II-IV heart disease
• No congestive heart failure
• No severe peripheral vascular disease
• No peripheral vascular disease with diabetes mellitus
• No deep venous or arterial thrombosis (including pulmonary embolism) within the past 3 months

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Fibrin split products less than 2 times normal
• Fibrinogen greater than 200 mg/dL
• No active uncontrolled bacterial, viral, or fungal infection
• No known hypersensitivity to E. coli-derived proteins
• No contraindications to limb-salvage surgery
• No other prior or concurrent malignancy within the past 5 years except surgically treated carcinoma in situ of the cervix or squamous or basal cell skin cancer
• No other serious medical or psychiatric illness that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior biologic therapy

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy

Surgery:

• More than 2 weeks since minor surgery
• More than 4 weeks since major surgery