Sorafenib, Epirubicin, Ifosfamide, and Radiation Therapy Followed By Surgery in Treating Patients With High-Risk Stage II or Stage III Soft Tissue Sarcoma
Condition: Sarcoma
MeSH terms: Sarcoma
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): epirubicin hydrochloride; ifosfamide; sorafenib tosylate; immunoenzyme technique; immunohistochemistry staining method; laboratory biomarker analysis; adjuvant therapy; neoadjuvant therapy; therapeutic conventional surgery; hypofractionated radiation therapy
Intervention type(s): Drug; Drug; Drug; Other; Other; Other; Procedure; Procedure; Procedure; Radiation
Intervention description(s): I.V., days 1-3 of each cycle. Epirubicin to be omitted during cycle 2 (concomitant chemoradiation); Over 90 minutes I.V., days 1-3 of each cycle. Administered with hydration and Mesna.; P.O. daily beginning 2 weeks before first chemotherapy cycle, held 1 week before and after surgery.; Preoperative administration has been the preference at our institution.; Surgery should be planned for 2-4 weeks after the initiation of chemotherapy for cycle 3.; 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.
Other intervention name(s): Adjuvant radiotherapy; Adjuvant chemotherapy; Neoadjuvant chemoradiotherapy
Intervention MeSH terms: Sorafenib; Epirubicin; Ifosfamide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: stage II adult soft tissue sarcoma; stage III adult soft tissue sarcoma