Sorafenib Tosylate, Combination Chemotherapy, Radiation Therapy, and Surgery in Treating Patients With High-Risk Stage IIB-IV Soft Tissue Sarcoma

PRIMARY OBJECTIVES:

I. To determine the pathologic response rate (>= 95% necrosis) after preoperative treatment
with sorafenib (sorafenib tosylate), epirubicin (epirubicin hydrochloride), ifosfamide, and
hypofractionated radiation for high risk soft tissue sarcomas of the extremities or body
wall.

SECONDARY OBJECTIVES:

I. To further characterize the safety of sorafenib plus chemoradiotherapy, including wound
complication rate.

II. To estimate time-to-event rates, including overall survival, overall disease-free
survival, distant disease-free survival, and local disease-free survival in patients with
high risk soft tissue sarcomas of the extremities or body wall treated with preoperative
sorafenib plus chemoradiotherapy and postoperative sorafenib plus chemotherapy.

OUTLINE:

Patients receive sorafenib tosylate orally (PO) once daily (QD) on days 1-71 and 85-155,
epirubicin hydrochloride intravenously (IV) over 3-5 minutes, and ifosfamide IV over 90
minutes on days 15-17, 36-38 (ifosfamide only), 57-59, 99-101, 120-122, and 141-143. Patients
undergo external beam radiation therapy (EBRT) on days 36-45 and surgical resection on day
78. Patients with positive margins, undergo EBRT boost on days 91-98.

After completion of study treatment, patients are followed up every 4 months for 2 years,
every 6 months for 1 year, and then yearly for 2 years.

Inclusion Criteria:

- Histologically confirmed, soft-tissue sarcoma: excluding rhabdomyosarcoma (pleomorphic
rhabdomyosarcoma patients are eligible), Ewing's, primitive neuroectodermal tumor
(PNET), osteosarcoma, or gastrointestinal stromal tumor

- American Joint Committee on Cancer (AJCC) (7th edition) stage IIb, III, or IV patients
planned for resection of the primary tumor

- > 5 cm in greatest dimension

- Intermediate or high-grade

- Superficial or deep

- Sarcoma located on upper (includes shoulder) or lower (includes hip) extremities or on
body wall

- Intermediate or high-grade: grades 2 or 3 on scale of 1-3

- Left ventricular ejection fraction (LVEF) >= 50%

- Absolute neutrophil count (ANC) >= 1500/uL

- Hemoglobin (Hgb) >= 9.0 g/dL

- Platelets >= 100,000/uL

- Creatinine =< 1.5 x upper limit of normal (ULN)

- Bilirubin =< 1.5 mg/dL

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 1.5 x ULN

- International normalized ratio (INR) < 1.5 or a prothrombin time (PT)/partial
thromboplastin time (PTT) within normal limits; patients receiving anti-coagulation
treatment with an agent such as warfarin or heparin may be allowed to participate; for
patients on warfarin, the INR should be measured prior to initiation of sorafenib and
monitored at least weekly, or as defined by the local standard of care, until INR is
stable

- No prior chemotherapy, radiation, or biotherapy

- No major surgery within 4 weeks prior to study entry

- No contraindications to limb-sparing surgery; patient should be evaluated by a surgeon
who specializes in sarcoma resections prior to study enrollment to ensure patient (pt)
is a candidate for limb-sparing surgery

- No severe peripheral vascular disease

- Adequate contraception must be used and patients must not be pregnant or
breastfeeding; women of childbearing potential and men must agree to use adequate
contraception (barrier method of birth control) prior to study entry and for the
duration of study participation; men and women should use adequate birth control for
at least thirty days after the last administration of sorafenib

- Women of childbearing potential must have negative serum pregnancy test performed
within 7-days prior to registration

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

- Patient must sign a study-specific consent form prior to registration

- Ability to understand and the willingness to sign a written informed consent; a signed
informed consent must be obtained prior to any study specific procedures

Exclusion Criteria:

- Patients with known brain metastases; patients with neurological symptoms must undergo
a computed tomography (CT) scan/magnetic resonance imaging (MRI) of the brain to
exclude brain metastases

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
serious infection > Common Terminology Criteria for Adverse Events (CTCAE) grade 2,
symptomatic congestive heart failure, unstable angina pectoris, cardiac ventricular
arrhythmia requiring anti-arrhythmic therapy, or psychiatric illness/social situations
that would limit compliance with study requirements; patients must not have unstable
angina (angina symptoms at rest) or new onset angina (began within the last 3 months)
or myocardial infarction within the past 6 months

- Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic
pressure > 90 mmHg, despite optimal medical management

- Known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C

- Thrombolic or embolic events such as a cerebrovascular accident including transient
ischemic attacks within the past 6 months

- Pulmonary hemorrhage/bleeding event >= CTCAE grade 2 within 4 weeks of first dose of
study drug

- Any other hemorrhage/bleeding event >= CTCAE grade 3 within 4 weeks of first dose of
study drug

- Serious non-healing wound, ulcer, or bone fracture

- Evidence or history of bleeding diathesis or coagulopathy

- Major surgery or significant traumatic injury within 4 weeks of first study drug

- Use of strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers

- Known or suspected allergy to sorafenib or any agent given in the course of this trial

- Any condition that impairs patient's ability to swallow whole pills

- Any malabsorption problem

- Pregnant or lactating women are excluded from this study

- Patients with a "currently active" second malignancy other than non-melanoma skin
cancers are not to be registered; patients are not considered to have a "currently
active" malignancy if they have completed therapy and considered by their physician to
be at less than 30% risk of relapse

- Any uncontrolled thyroid disease

- Requirement for hemodialysis or peritoneal dialysis