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Phase I/II Trial of Neoadjuvant Conformal Radiotherapy Plus Sorafenib for Patients With Soft Tissue Sarcoma of the Extremity and Body Wall

Phase 1/Phase 2
18 Years
Not Enrolling
Soft Tissue Sarcoma

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Trial Information

Phase I/II Trial of Neoadjuvant Conformal Radiotherapy Plus Sorafenib for Patients With Soft Tissue Sarcoma of the Extremity and Body Wall

Patients will receive neoadjuvant sorafenib (investigational agent) in combination with
preoperative external beam conformal radiotherapy (50 Gy in 25 fractions) for localized,
large soft tissue sarcomas of the extremity and body wall prior to resection with curative
intent. Sorafenib is an FDA-approved targeted agent for patients with renal cell carcinoma
and hepatocellular carcinoma. Preliminary data suggest activity for sorafenib against soft
tissue sarcoma in the metastatic setting. Limited data are available regarding the safety
and efficacy of sorafenib in combination with radiotherapy.

The Phase I portion of the trial will seek to establish the safety of sorafenib and
radiotherapy in the neoadjuvant setting for soft tissue sarcomas of the extremity and body
wall. The Phase II portion of the trial will aim to determine the pathologic
near-complete/complete response rate (≥ 95% tumor necrosis) of this multimodality therapy.
Molecular and dynamic contrast-enhanced MRI studies will seek to establish correlative
biological and imaging markers of response and/or resistance to this therapy.

Significant challenges exist in the treatment of patients with soft tissue sarcoma (STS) of
the extremity and body wall. Major therapeutic goals for all patients include local
disease-control, maximization of limb function, and avoidance of therapeutic morbidity. The
standard approach for patients with STS has been based on radical resection with wide
margins in combination with external beam radiation. Although local control rates in this
setting range from 85 to 90%, patients remain at risk for substantial morbidity from this
multimodality therapy. Furthermore, despite effective local therapy with surgery and
radiation, approximately 50% of patients with high grade STS will die of disease within 5
years of diagnosis.

Experimental data and experience from other solid tumors suggest a significant synergistic
effect when anti-angiogenic targeted therapies, such as sorafenib, are combined with
radiotherapy (RT). Overproduction of angiogenic factors in the tumor vasculature leads to
disordered/poorly regulated tumor perfusion which appears to normalize following delivery of
anti-angiogenic agents. This, in turn, allows improved delivery of and susceptibility to
cytotoxic agents, which is particularly important with RT since hypoxia is a key mechanism
of resistance to this modality. Preliminary clinical data in rectal cancer and malignant
brain tumors have demonstrated promising results from the combination of anti-angiogenic
agents and RT with respect to downstaging of the primary tumor, local tumor control, and
improved progression-free survival. Angiogenic factors are upregulated in patients with STS,
and anti-angiogenic agents demonstrate activity against STS in the metastatic setting.

Consequently, we propose to evaluate preoperative combined modality sorafenib and conformal
RT in patients with STS of the extremity and body wall in a prospective Phase I/II clinical
trial. Key endpoints will be safety and toxicity in the Phase I trial and pathological
response in the Phase II trial. Additional endpoints will include molecular and functional
imaging correlative studies of biomarkers of response and resistance to treatment.

We hypothesize that this combination will be safe and will increase pathologic necrosis
within the primary tumor at the time of surgical resection, translating into reduced volume
of resected tissue, improved local disease-control, and ultimately improved disease-free
survival. Functional imaging studies (dynamic contrast-enhanced MRI) and molecular
examination of pre- and post-treatment tumor tissue and serum will allow correlation of
changes in tumor blood flow, hypoxia transcription factors, phosphorylated ERK, and
angiogenic markers to the degree of tumor necrosis following treatment with preoperative
sorafenib and radiotherapy.

Inclusion Criteria:

- Histologically confirmed soft-tissue sarcoma located on the extremity or body wall.

- Intermediate or High grade (NCI grade 2 or 3/3-tier system), > 5 cm in maximal

- Low grade (NCI grade 1/3-tier system), > 8 cm in maximal dimension.

- No evidence of regional or distant metastatic disease.

- Patient must be 18 years of age or older.

- Patient must have an ECOG performance status of ≤ 2.

- Patient must have a histologic diagnosis of soft tissue sarcoma.

- Patient must have adequate bone marrow, liver, and renal function as assessed by the

- Hemoglobin ≥ 9.0 g/dl

- Absolute neutrophil count (ANC) ≥ 1,500/mm3

- Platelets ≥ 100,000/mm3.

- Total bilirubin ≤ 1.5 mg/dL. NOTE: Patients with elevated bilirubin secondary
to Gilbert's syndrome are eligible to participate in the study.

- AST and ALT ≤ 2.5 times the institution upper limit of normal (ULN).

- Creatinine ≤ 1.5 times ULN.

- Females of childbearing potential must have a negative serum pregnancy test within 7
days prior to the start of treatment . NOTE: Postmenopausal women must be amenorrheic
for at least 12 months to be deemed not of reproductive potential.

- Women of childbearing potential and men must agree to use adequate contraception
(barrier method of birth control) prior to study entry and for the duration of study
participation. Men should use adequate birth control for at least three months after
the last administration of sorafenib.

- Ability to understand and the willingness to sign a written informed consent. A
signed informed consent must be obtained prior to any study specific procedures.

- INR < 1.5 or a PT/PTT within normal limits. Patients receiving anti-coagulation
treatment with an agent such as warfarin or heparin may be allowed to participate.
For patients on warfarin, the INR should be measured prior to initiation of sorafenib
and monitored at least weekly, or as defined by the local standard of care, until INR
is stable.

Exclusion Criteria:

- Patient is receiving additional cancer-directed therapy at time of entry into trial.

- Patient has received or is receiving preoperative investigational treatment.

- Patient has congestive heart failure > class II NYHA. Patients must not have
unstable angina (anginal symptoms at rest) or new onset angina (began within the last
3 months) or myocardial infarction within the past 6 months.

- Patient has history of cardiac ventricular arrhythmia requiring ongoing
anti-arrhythmic therapy.

- Patient has uncontrolled hypertension, defined as systolic blood pressure > 150 mmHg
or diastolic pressure > 90 mmHg, despite optimal medical management.

- Patient has known human immunodeficiency virus (HIV) infection or chronic Hepatitis B
or C.

- Patient has active clinically serious infection > CTCAE Grade 2.

- Patient has thrombotic or embolic events such as a cerebrovascular accident including
transient ischemic attacks within the past 6 months.

- Patient has history of pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4
weeks of first dose of study drug.

- Patient has history of any other hemorrhage/bleeding event > CTCAE Grade 3 within 4
weeks of first dose of study drug.

- Patient has history of clinical or laboratory evidence of bleeding diathesis or

- Patient has history of major surgery or significant traumatic injury within 4 weeks
of first study drug.

- Patient has concomitant use of St. John's Wort or rifampin (rifampicin).

- Patient has known or suspected allergy to sorafenib or any agent given in the course
of this trial.

- Patient has any condition that impairs his or her ability to swallow whole pills.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of Dose Limiting Toxicities

Outcome Description:

Number of dose limiting toxicities and number with adverse events. Dose-escalation schedule comprising 6 to 12 patients (see schema). This sample size is based on a traditional 3+3 cohort design with escalating doses of sorafenib in combination with 50 Gy of conformal radiotherapy delivered in 25 fractions (200 cGy per fraction). Based on preclinical data regarding the radiobiology of sorafenib,33, 36 sorafenib will be initiated at a dose of 200 mg twice daily, followed by 200 mg Q AM/400 mg Q PM for the 2nd cohort, followed by 400 mg bid for the 3rd cohort. Since 400 mg bid is the well established MTD for sorafenib monotherapy in patients with renal cell carcinoma and hepatocellular carcinoma, the dose will not be escalated above this level even if DLT is not observed. Dose level escalation will be determined based on DLTs observed from initiation of sorafenib/RT until time of surgery.

Outcome Time Frame:

Approximately 12 weeks

Safety Issue:


Principal Investigator

Robert Canter, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

U C Davis Medical Center


United States: Food and Drug Administration

Study ID:

STS Sorafenib



Start Date:

March 2009

Completion Date:

August 2011

Related Keywords:

  • Soft Tissue Sarcoma
  • Soft tissue sarcoma of the extremity and body wall
  • Sarcoma



University of California, Davis Medical Center Sacramento, California