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
- 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 p-ERK, VEGF,
sVEGFR-2, and bFGF, in plasma and tumor tissue samples at baseline and during and after
- To evaluate expression of tumor proliferation and angiogenic factors, including p-ERK,
VEGFR2 and PDGFR, in tumor tissue samples as measured by 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, sVEGFR2, and bFGF. Tumor tissue
samples are also analyzed by IHC for p-ERK, VEGFR2, phospho-VEGFR2, PDGFR, and
After completion of study therapy, patients are followed periodically.
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose of sorafenib tosylate when combined with chemoradiotherapy
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.
The first 8 weeks of therapy, but dose limiting toxicity (DLTs) will be monitored throughout the entire 22 week treatment
Christopher W. Ryan, MD
OHSU Knight Cancer Institute
United States: Food and Drug Administration
|OHSU Knight Cancer Institute||Portland, Oregon 97239|