Sorafenib, Epirubicin, Ifosfamide, and Radiation Therapy Followed By Surgery in Treating Patients With High-Risk Stage II or Stage III Soft Tissue Sarcoma
- Conditions
- Sarcoma
- Interventions
- Other: immunoenzyme techniqueOther: immunohistochemistry staining methodOther: laboratory biomarker analysisProcedure: adjuvant therapyProcedure: neoadjuvant therapyProcedure: therapeutic conventional surgeryRadiation: hypofractionated radiation therapy
- Registration Number
- NCT00822848
- Lead Sponsor
- OHSU Knight Cancer Institute
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 18
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Sorafenib, Epirubicin, Ifosfamide laboratory biomarker analysis - Sorafenib, Epirubicin, Ifosfamide immunohistochemistry staining method - Sorafenib, Epirubicin, Ifosfamide epirubicin hydrochloride - Sorafenib, Epirubicin, Ifosfamide ifosfamide - Sorafenib, Epirubicin, Ifosfamide sorafenib tosylate - Sorafenib, Epirubicin, Ifosfamide immunoenzyme technique - Sorafenib, Epirubicin, Ifosfamide adjuvant therapy - Sorafenib, Epirubicin, Ifosfamide neoadjuvant therapy - Sorafenib, Epirubicin, Ifosfamide therapeutic conventional surgery - Sorafenib, Epirubicin, Ifosfamide hypofractionated radiation therapy -
- Primary Outcome Measures
Name Time Method Maximum tolerated dose (MTD) of sorafenib tosylate when combined with chemoradiotherapy The first 8 weeks of therapy, but dose limiting toxicity (DLTs) will be monitored throughout the entire 22 week treatment 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.
Safety As necessary and at the discretion of the principal investigator 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).
- Secondary Outcome Measures
Name Time Method Distant disease-free survival Registration until development of distant metastatic disease or death, whichever occurs first. 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.
Time to local recurrence From surgical resection of the primary tumor until local recurrence Defined as the duration of time from surgical resection of the primary tumor until local recurrence (amputated patients excluded).
Histologic necrosis rate of ≥ 95% Examined for pathologic response at the time of surgery. 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. Progression-free survival Registration to progressive disease (per RECIST) 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.
Overall survival Registration until death from any cause. Defined as the interval of time from registration until death from any cause.
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
Trial Locations
- Locations (1)
OHSU Knight Cancer Institute
🇺🇸Portland, Oregon, United States