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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


Phase 1
15 Years
N/A
Open (Enrolling)
Both
Sarcoma

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Trial Information

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


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 p-ERK, VEGF,
sVEGFR-2, and 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,
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
phospho-PDGFR.

After completion of study therapy, patients are followed periodically.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed soft tissue sarcoma of the upper (including shoulder) or
lower (including hip) extremities or body wall

- Stage II or III disease, as defined by the following:

- Tumor dimension > 5 cm

- Superficial or deep tumor

- Intermediate or high-grade disease

- No regional lymph node involvement

- No distant metastases

- No rhabdomyosarcoma, Ewing sarcoma, primitive neuroectodermal tumor (PNET),
osteosarcoma, or gastrointestinal stromal tumor

- Pleomorphic rhabdomyosarcoma allowed

- No known metastases

- Patients with neurological symptoms must undergo a CT scan or MRI of the brain
to exclude brain metastases

PATIENT CHARACTERISTICS:

- ECOG performance status 0-1

- ANC ≥ 1,500/μL

- Hemoglobin ≥ 9.0 g/dL

- Platelet count ≥ 100,000/μL

- INR < 1.5 or PT/PTT normal

- Creatinine ≤ 1.5 times upper limit of normal (ULN)

- Bilirubin ≤ 1.5 mg/dL

- AST/ALT ≤ 1.5 times ULN

- LVEF ≥ 50%

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception (male patients must use effective
contraception for ≥ 3 months after completion of study treatment)

- No contraindications to limb-sparing surgery

- No severe peripheral vascular disease

- No concurrent uncontrolled illness including, but not limited to, the following:

- Ongoing or active serious infection > CTCAE grade 2

- Symptomatic congestive heart failure

- Unstable angina pectoris (i.e., angina symptoms at rest) or new onset angina
within the past 3 months

- Myocardial infarction within the past 6 months

- Cardiac ventricular arrhythmia requiring anti-arrhythmic therapy

- Psychiatric illness/social situation that would limit compliance with study
requirements

- No uncontrolled hypertension (defined as systolic blood pressure > 150 mm Hg or
diastolic blood pressure > 90 mm Hg, despite optimal medical management)

- No known HIV infection or chronic hepatitis B or C infection

- No thrombolic or embolic events (e.g., cerebrovascular accident, including transient
ischemic attacks) within the past 6 months

- No pulmonary hemorrhage or bleeding event ≥ CTCAE grade 2 within the past 4 weeks

- No other hemorrhage or bleeding event ≥ CTCAE grade 3 within the past 4 weeks

- No serious non-healing wound, ulcer, or bone fracture

- No evidence or history of bleeding diathesis or coagulopathy

- No significant traumatic injury within the past 4 weeks

- No known or suspected allergy to sorafenib tosylate or any agent given in the study

- No condition that would impair the ability to swallow whole pills

- No malabsorption problem

- No "currently active" second malignancy other than non-melanoma skin cancer

- Not considered to have a "currently active" malignancy if patient completed
therapy AND has a < 30% risk of relapse

PRIOR CONCURRENT THERAPY:

- No prior chemotherapy, radiotherapy, or biotherapy

- More than 4 weeks since prior major surgery

- No concurrent St. John's wort or rifampin

- No other concurrent investigational or anticancer therapy

- Concurrent anticoagulation with warfarin or heparin allowed

Type of Study:

Interventional

Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of sorafenib tosylate when combined with chemoradiotherapy

Outcome Description:

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.

Outcome Time Frame:

The first 8 weeks of therapy, but dose limiting toxicity (DLTs) will be monitored throughout the entire 22 week treatment

Safety Issue:

Yes

Principal Investigator

Christopher W. Ryan, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

OHSU Knight Cancer Institute

Authority:

United States: Food and Drug Administration

Study ID:

CDR0000631580

NCT ID:

NCT00822848

Start Date:

February 2009

Completion Date:

Related Keywords:

  • Sarcoma
  • stage II adult soft tissue sarcoma
  • stage III adult soft tissue sarcoma
  • Sarcoma

Name

Location

OHSU Knight Cancer InstitutePortland, Oregon  97239