Sorafenib, Epirubicin, Ifosfamide, and Radiation Therapy Followed By Surgery in Treating Patients With High-Risk Stage II or Stage III Soft Tissue Sarcoma

OBJECTIVES:

Primary

- To determine the maximum tolerated dose of sorafenib tosylate when combined with
epirubicin hydrochloride, ifosfamide, and hypofractionated radiotherapy prior to surgery
in patients with high-risk stage II or III soft tissue sarcoma of the extremity or body
wall.

Secondary

- To examine, preliminarily, the activity of this regimen, in terms of time to local
recurrence, distant disease-free survival, progression-free survival, overall survival,
and histologic necrosis rate of ≥ 95%, in these patients.

- To investigate levels of tumorigenic and angiogenic markers, including phosphorylated
extracellular signal-regulated kinase (p-ERK), vascular endothelial growth factor
(VEGF), serum vascular endothelial growth factor receptor-2 (sVEGFR-2), and basic
fibroblast growth factor (bFGF), in plasma and tumor tissue samples at baseline and
during and after treatment.

- To evaluate expression of tumor proliferation and angiogenic factors, including p-ERK,
vascular endothelial growth factor receptor-2 (VEGFR2) and Platelet-derived growth
factor receptor (PDGFR), in tumor tissue samples as measured by Immunohistochemistry
(IHC).

OUTLINE: This is a dose-escalation study of sorafenib tosylate.

Patients receive oral sorafenib tosylate* once or twice daily beginning 2 weeks before the
initiation of chemotherapy and continuing until the completion of chemotherapy. Patients also
receive epirubicin hydrochloride** IV and ifosfamide IV over 90 minutes on days 1-3 and
pegfilgrastim subcutaneously (SC) on day 4 or filgrastim (G-CSF) (SC) daily beginning on day
4 and continuing for up to 10 days or until blood counts recover. Chemotherapy repeats
approximately every 21 days for 6 courses in the absence of disease progression or
unacceptable toxicity. During course 2, patients also undergo 8 fractions of external beam
radiotherapy once daily between days 1-10 for a total dose of 28 Gy. Between courses 3 and 4,
patients undergo surgical resection. Beginning approximately 2 weeks after surgical
resection, patients with positive surgical margins undergo 6 fractions of boost external beam
radiotherapy once daily for a total dose of 12 Gy.

NOTE: *Sorafenib is discontinued 1 week before surgery and resumed 1 week after surgery.

NOTE: **Epirubicin is omitted during course 2.

Plasma and tumor tissue samples are collected periodically for correlative laboratory
studies. Plasma and tumor tissue samples are analyzed by ELISA for measurement of tumorigenic
and angiogenic markers, including p-ERK, VEGF, sVEGFR-2, and bFGF. Tumor tissue samples are
also analyzed by IHC for p-ERK, VEGFR2, phospho-VEGFR2, PDGFR, and phospho-PDGFR.

After completion of study therapy, patients are followed periodically.

DISEASE CHARACTERISTICS:

- Histologically confirmed soft tissue sarcoma of the upper (including shoulder) or
lower (including hip) extremities or body wall

- Stage II or III disease, as defined by the following:

- Tumor dimension > 5 cm

- Superficial or deep tumor

- Intermediate or high-grade disease

- No regional lymph node involvement

- No distant metastases

- No rhabdomyosarcoma, Ewing sarcoma, primitive neuroectodermal tumor (PNET),
osteosarcoma, or gastrointestinal stromal tumor

- Pleomorphic rhabdomyosarcoma allowed

- No known metastases

- Patients with neurological symptoms must undergo a CT scan or MRI of the brain to
exclude brain metastases

PATIENT CHARACTERISTICS:

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Absolute Neutrophil Count (ANC) ≥ 1,500/μL

- Hemoglobin ≥ 9.0 g/dL

- Platelet count ≥ 100,000/μL

- International Normalized Ratio (INR) < 1.5 or Prothrombin Time/Partial Thromboplastin
Time (PT/PTT) normal

- Creatinine ≤ 1.5 times upper limit of normal (ULN)

- Bilirubin ≤ 1.5 mg/dL

- Aspartate Aminotransferase/Alanine Aminotransferase (AST/ALT) ≤ 1.5 times ULN

- Left Ventricular Ejection Fraction (LVEF) ≥ 50%

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception (male patients must use effective
contraception for ≥ 3 months after completion of study treatment)

- No contraindications to limb-sparing surgery

- No severe peripheral vascular disease

- No concurrent uncontrolled illness including, but not limited to, the following:

- Ongoing or active serious infection > Common Toxicity Criteria for Adverse
Effects (CTCAE) grade 2

- Symptomatic congestive heart failure

- Unstable angina pectoris (i.e., angina symptoms at rest) or new onset angina
within the past 3 months

- Myocardial infarction within the past 6 months

- Cardiac ventricular arrhythmia requiring anti-arrhythmic therapy

- Psychiatric illness/social situation that would limit compliance with study
requirements

- No uncontrolled hypertension (defined as systolic blood pressure > 150 mm Hg or
diastolic blood pressure > 90 mm Hg, despite optimal medical management)

- No known HIV infection or chronic hepatitis B or C infection

- No thrombolic or embolic events (e.g., cerebrovascular accident, including transient
ischemic attacks) within the past 6 months

- No pulmonary hemorrhage or bleeding event ≥ CTCAE grade 2 within the past 4 weeks

- No other hemorrhage or bleeding event ≥ CTCAE grade 3 within the past 4 weeks

- No serious non-healing wound, ulcer, or bone fracture

- No evidence or history of bleeding diathesis or coagulopathy

- No significant traumatic injury within the past 4 weeks

- No known or suspected allergy to sorafenib tosylate or any agent given in the study

- No condition that would impair the ability to swallow whole pills

- No malabsorption problem

- No "currently active" second malignancy other than non-melanoma skin cancer

- Not considered to have a "currently active" malignancy if patient completed
therapy AND has a < 30% risk of relapse

PRIOR CONCURRENT THERAPY:

- No prior chemotherapy, radiotherapy, or biotherapy

- More than 4 weeks since prior major surgery

- No concurrent St. John's wort or rifampin

- No other concurrent investigational or anticancer therapy

- Concurrent anticoagulation with warfarin or heparin allowed