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
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- OHSU Knight Cancer Institute
- Enrollment
- 18
- Locations
- 1
- Primary Endpoint
- Maximum tolerated dose (MTD) of sorafenib tosylate when combined with chemoradiotherapy
Study Overview
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).
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 15 Years to 120 Years (Child, Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Sorafenib, Epirubicin, Ifosfamide
Intervention: epirubicin hydrochloride (Drug)
Sorafenib, Epirubicin, Ifosfamide
Intervention: ifosfamide (Drug)
Sorafenib, Epirubicin, Ifosfamide
Intervention: laboratory biomarker analysis (Other)
Sorafenib, Epirubicin, Ifosfamide
Intervention: sorafenib tosylate (Drug)
Sorafenib, Epirubicin, Ifosfamide
Intervention: immunoenzyme technique (Other)
Sorafenib, Epirubicin, Ifosfamide
Intervention: immunohistochemistry staining method (Other)
Sorafenib, Epirubicin, Ifosfamide
Intervention: adjuvant therapy (Procedure)
Sorafenib, Epirubicin, Ifosfamide
Intervention: neoadjuvant therapy (Procedure)
Sorafenib, Epirubicin, Ifosfamide
Intervention: therapeutic conventional surgery (Procedure)
Sorafenib, Epirubicin, Ifosfamide
Intervention: hypofractionated radiation therapy (Radiation)
Outcomes
Primary Outcomes
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
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
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 Outcomes
- Distant disease-free survival(Registration until development of distant metastatic disease or death, whichever occurs first.)
- Time to local recurrence(From surgical resection of the primary tumor until local recurrence)
- 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))
- Overall survival(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)
Investigators
Christopher Ryan
Principal Investigator
OHSU Knight Cancer Institute