Sorafenib, Epirubicin, Ifosfamide, and Radiation Therapy Followed By Surgery in Treating Patients With High-Risk Stage II or Stage III Soft Tissue Sarcoma
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.
Drug: epirubicin hydrochloride
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
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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|
- Maximum tolerated dose (MTD) of sorafenib tosylate when combined with chemoradiotherapy [ Time Frame: The first 8 weeks of therapy, but dose limiting toxicity (DLTs) will be monitored throughout the entire 22 week treatment ] [ Designated as safety issue: Yes ]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 [ Time Frame: As necessary and at the discretion of the principal investigator ] [ Designated as safety issue: Yes ]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).
- Time to local recurrence [ Time Frame: From surgical resection of the primary tumor until local recurrence ] [ Designated as safety issue: No ]Defined as the duration of time from surgical resection of the primary tumor until local recurrence (amputated patients excluded).
- Distant disease-free survival [ Time Frame: Registration until development of distant metastatic disease or death, whichever occurs first. ] [ Designated as safety issue: No ]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.
- Progression-free survival [ Time Frame: Registration to progressive disease (per RECIST) ] [ Designated as safety issue: No ]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 [ Time Frame: Registration until death from any cause. ] [ Designated as safety issue: No ]Defined as the interval of time from registration until death from any cause.
- Histologic necrosis rate of ≥ 95% [ Time Frame: Examined for pathologic response at the time of surgery. ] [ Designated as safety issue: No ]
- Levels of tumorigenic and angiogenic markers, including p-ERK, VEGF, sVEGFR-2, bFGF, in plasma and tumor tissue samples as measured by ELISA [ Time Frame: Baseline, during, and after treatment with sorafenib plus chemoradiotherapy ] [ Designated as safety issue: No ]
- Expression of tumor proliferation and angiogenic factors, including p-ERK, VEGFR2 and PDGFR, in tumor tissue samples as measured by IHC [ Time Frame: baseline, week 2 (after sorafenib run-in), and then every 3 weeks through completion of treatment. ] [ Designated as safety issue: No ]
|Study Start Date:||February 2009|
|Primary Completion Date:||September 2012 (Final data collection date for primary outcome measure)|
|Experimental: Sorafenib, Epirubicin, Ifosfamide||
Drug: epirubicin hydrochloride
I.V., days 1-3 of each cycle. Epirubicin to be omitted during cycle 2 (concomitant chemoradiation)Drug: ifosfamide
Over 90 minutes I.V., days 1-3 of each cycle. Administered with hydration and Mesna.Drug: sorafenib tosylate
P.O. daily beginning 2 weeks before first chemotherapy cycle, held 1 week before and after surgery.Other: immunoenzyme technique Other: immunohistochemistry staining method Other: laboratory biomarker analysis Procedure: adjuvant therapy
Preoperative administration has been the preference at our institution.
Other Names:Procedure: neoadjuvant therapy
Other Name: Neoadjuvant chemoradiotherapyProcedure: therapeutic conventional surgery
Surgery should be planned for 2-4 weeks after the initiation of chemotherapy for cycle 3.Radiation: hypofractionated radiation therapy
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.
- 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.
- 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00822848
|United States, Oregon|
|OHSU Knight Cancer Institute|
|Portland, Oregon, United States, 97239-3098|
|Principal Investigator:||Christopher W. Ryan, MD||OHSU Knight Cancer Institute|