Combination Chemotherapy and Dexrazoxane Followed by Surgery and Radiation Therapy in Treating Patients With Advanced Soft Tissue Sarcoma or Recurrent Bone Sarcoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as doxorubicin, ifosfamide, and irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Chemoprotective drugs, such as dexrazoxane, may protect normal cells from the side effects of chemotherapy. Giving combination chemotherapy together with dexrazoxane before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving radiation therapy after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying how well giving combination chemotherapy together with dexrazoxane followed by surgery and radiation therapy works in treating patients with advanced soft tissue sarcoma or recurrent bone sarcoma.

Detailed Description
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OBJECTIVES: To evaluate the effectiveness of neoadjuvant dose-dense chemotherapy comprising doxorubicin hydrochloride, ifosfamide, and irinotecan hydrochloride in combination with dexrazoxane hydrochloride followed by surgery and radiotherapy in patients with advanced soft tissue sarcoma or recurrent bone sarcoma. To evaluate the toxicities of this regimen in these patients. To compare the duration of disease-free and overall survival of patients with advanced soft tissue sarcoma who receive this therapy on a neoadjuvant basis with historical controls. To evaluate laboratory correlates of chemotherapy resistance for the cytotoxic agents used in this study. OUTLINE: Patients are stratified by type of sarcoma (soft tissue vs bone), prior treatment (untreated vs treated), and presence of metastases (yes vs no). Courses 1 and 2: Patients receive doxorubicin hydrochloride and dexrazoxane hydrochloride IV continuously over 96 hours. Treatment repeats every 3 weeks for 2 courses. Courses 3 and 4: Patients receive ifosfamide IV over 2 hours twice a day (every 12 hours) on days 1-3. Treatment repeats every 3 weeks for 2 courses. Courses 5 and 6: Patients receive irinotecan hydrochloride IV over 1 hour once a day on days 1-5 and 8-12. Treatment repeats every 3 weeks for 2 courses. Patients also receive filgrastim (G-CSF) subcutaneously once a day beginning 3 days after completion of chemotherapy and continuing until blood counts recover. Patients then undergo standard surgery and radiotherapy. Patients undergo blood sample collection periodically for correlative studies. Samples are analyzed for MDR (multidrug resistance gene) protein expression via immunoperoxidase staining. After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 2 years, and then once a year thereafter.

Official Title
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Phase II Trial of Neoadjuvant Dose-Dense Doxorubicin, Ifosfamide, and Irinotecan (CPT-11) for Advanced Soft Tissue and Recurrent Bone Sarcomas

Conditions
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Sarcoma

Intervention / Treatment
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* Biological: filgrastim
* Drug: dexrazoxane hydrochloride
* Drug: doxorubicin hydrochloride
* Drug: ifosfamide
* Drug: irinotecan hydrochloride
* Genetic: protein expression analysis
* Other: immunoenzyme technique
* Procedure: adjuvant therapy
* Procedure: conventional surgery
* Procedure: neoadjuvant therapy
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of 1 of the following: Primary soft tissue sarcoma at high-risk* for recurrence, meeting any of the following criteria: Previously untreated locally advanced, nonmetastatic disease Advanced (metastatic) disease not amenable to standard or higher priority investigational neoadjuvant therapies Recurrent bone sarcoma (e.g., osteogenic sarcoma, Ewing sarcoma, or peripheral neuroectodermal tumor) Must have advanced locally recurrent or metastatic disease NOTE: *High-risk is defined as high-grade, deep to fascia, and > 5 cm in greatest dimension Measurable or nonmeasurable disease is not required Pre-chemotherapy consultation with surgery and radiation oncology is required for formulation of loco-regional therapy No gastrointestinal stromal cell sarcoma No alveolar soft part sarcoma No symptomatic brain metastases No requirement for anticonvulsant or corticosteroid therapy PATIENT CHARACTERISTICS: Karnofsky performance status 70-100% Life expectancy ≥ 2 months Absolute neutrophil count ≥ 2,000/mm^3 Platelet count > 120,000/mm^3 Creatinine clearance > 50 mL/min Serum bilirubin ≤ 1.5 mg/dL SGOT or SGPT ≤ 2.5 times upper limit of normal Serum albumin ≥ 2.5 mg/dL LVEF ≥ 50% by MUGA scan Not pregnant or nursing Fertile patients must use effective contraception No concurrent nonmalignant illness (e.g., cardiovascular, pulmonary, or CNS disease) that is poorly controlled with currently available treatment or is of such severity that the investigators deem it unwise for the patient to enter the study PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior chemotherapy for recurrent (local or metastatic) soft tissue sarcoma Prior chemotherapy for recurrent bone sarcoma allowed provided the total dose of doxorubicin hydrochloride is ≤ 300 mg/m^2 No prior radiotherapy to > 25% of bone marrow At least 3 weeks since prior radiotherapy or chemotherapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>High-dose chemotherapy with doxorubicin at 120 mg/m2 and ifosfamide at 2 g/m2 followed by a prolonged schedule of CPT-11 at 20 mg/m2. | Biological: filgrastim<br> <br> Drug: dexrazoxane hydrochloride<br> <br> Drug: doxorubicin hydrochloride<br> <br> Drug: ifosfamide<br> <br> Drug: irinotecan hydrochloride<br> <br> Genetic: protein expression analysis<br> <br> Other: immunoenzyme technique<br> <br> Procedure: adjuvant therapy<br> <br> Procedure: conventional surgery<br> <br> Procedure: neoadjuvant therapy<br> <br> Radiation: radiation therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Response rate defined as the proportion of subjects with confirmed partial or complete response as defined by the RECIST criteria. | First disease evaluation one month after the start of treatment and every 3 months there after, up to 2 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult soft tissue sarcoma, stage III adult soft tissue sarcoma, stage IV adult soft tissue sarcoma, metastatic osteosarcoma, recurrent osteosarcoma, metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor, recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor, Ewing sarcoma of bone