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

Study Overview
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Brief Summary
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RATIONALE: 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. Drugs used in chemotherapy, such as epirubicin and ifosfamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving chemotherapy and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase I trial is studying the side effects and best dose of sorafenib when given together with epirubicin, ifosfamide, and radiation therapy followed by surgery in treating patients with high-risk stage II or stage III soft tissue sarcoma.

Detailed Description
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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.

Official Title
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Antiangiogenic Potentiation of Preoperative Chemoradiotherapy for High Risk Extremity Soft Tissue Sarcomas: A Phase I Study of Sorafenib With Epirubicin, Ifosfamide, Hypofractionated Radiation, and Surgery

Conditions
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Sarcoma

Intervention / Treatment
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* Drug: epirubicin hydrochloride
* Drug: ifosfamide
* Drug: sorafenib tosylate
* Other: immunoenzyme technique
* Other: immunohistochemistry staining method
* Other: laboratory biomarker analysis
* Procedure: adjuvant therapy
* Procedure: neoadjuvant therapy
* Procedure: therapeutic conventional surgery
* Radiation: hypofractionated radiation therapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib, Epirubicin, Ifosfamide<br> | Drug: epirubicin hydrochloride<br>* I.V., days 1-3 of each cycle. Epirubicin to be omitted during cycle 2 (concomitant chemoradiation)<br>Drug: ifosfamide<br>* Over 90 minutes I.V., days 1-3 of each cycle. Administered with hydration and Mesna.<br>Drug: sorafenib tosylate<br>* P.O. daily beginning 2 weeks before first chemotherapy cycle, held 1 week before and after surgery.<br>Other: immunoenzyme technique<br> <br> Other: immunohistochemistry staining method<br> <br> Other: laboratory biomarker analysis<br> <br> Procedure: adjuvant therapy<br>* Preoperative administration has been the preference at our institution.<br>* Other names: Adjuvant chemotherapy;Procedure: neoadjuvant therapy<br> <br> * Other names: Neoadjuvant chemoradiotherapy;Procedure: therapeutic conventional surgery<br>* Surgery should be planned for 2-4 weeks after the initiation of chemotherapy for cycle 3.<br>Radiation: hypofractionated radiation therapy<br>* 28 Gy (350 centigray (cGy) x 8 fractions in 10 days) beginning at the start of cycle 2. *Boost: postoperative boost of 12 Gy (200 cGy x 6 fractions) for patients with positive surgical margins only.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of sorafenib tosylate when combined with chemoradiotherapy | The MTD is defined as the dose that produces dose limiting toxicity (DLT) in 33% of patients. Dose level escalation will be determined based on DLTs observed through the first 8 weeks of therapy, but DLTs will be monitored throughout the entire 22 week treatment course and dose de-escalation may occur if excess late DLTs are observed. | The first 8 weeks of therapy, but dose limiting toxicity (DLTs) will be monitored throughout the entire 22 week treatment | 
| Safety | As necessary and at the discretion of the principal investigator, a given dose level may be expanded by 3-6 subjects to further explore the safety of that dose level upon prior written approval of the Institutional Review Board (IRB). | As necessary and at the discretion of the principal investigator | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to local recurrence | Defined as the duration of time from surgical resection of the primary tumor until local recurrence (amputated patients excluded). | From surgical resection of the primary tumor until local recurrence | 
| Distant disease-free survival | Defined as the duration of time from registration until development of distant metastatic disease or death, whichever occurs first. Subjects with stage IV disease will be censored from this analysis. | Registration until development of distant metastatic disease or death, whichever occurs first. | 
| Progression-free survival | Defined as the duration of time from registration to progressive disease (per RECIST), local recurrence, distant metastatic disease (exclusive of stage IV subjects), or death, whichever occurs first. | Registration to progressive disease (per RECIST) | 
| Overall survival | Defined as the interval of time from registration until death from any cause. | Registration until death from any cause. | 
| Histologic necrosis rate of ≥ 95% |  | Examined for pathologic response at the time of surgery. | 
| Levels of tumorigenic and angiogenic markers, including p-ERK, VEGF, sVEGFR-2, bFGF, in plasma and tumor tissue samples as measured by ELISA |  | Baseline, during, and after treatment with sorafenib plus chemoradiotherapy | 
| Expression of tumor proliferation and angiogenic factors, including p-ERK, VEGFR2 and PDGFR, in tumor tissue samples as measured by IHC |  | baseline, week 2 (after sorafenib run-in), and then every 3 weeks through completion of treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II adult soft tissue sarcoma, stage III adult soft tissue sarcoma