Trial of Cetuximab in Patients With Metastatic and/or Locally Advanced Soft Tissue and Bony Sarcomas

Study Overview
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Brief Summary
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The purpose of this study is to explore how this cancer is affected by a new medication, cetuximab. Cetuximab is directed towards a protein called EGFR (epidermal growth factor receptor), that is found in some types of cancer. Studies have shown that this drug can be beneficial in patients with colon cancer and has been approved by the US Food and Drug Administration (FDA) for this purpose. The researchers are conducting a study to see if it is beneficial in patients with sarcoma.

Detailed Description
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Sarcomas are mesenchymal malignancies that arise in the connective tissue throughout the body and afflict approximately 11,000 people in the United States yearly. Sarcomas are heterogeneous with well over 50 subtypes described. The peak incidence is subtype-specific with certain sarcomas seen in children and young adults while other subtypes peak in late middle-age, causing significant morbidity and mortality in young patients and productive adults. The precise etiology for most sarcomas remains unknown. External radiation therapy is an established risk factor. Other risk factors include occupational exposures to certain chemicals, lymphedema, and hereditary conditions such as neurofibromatosis and Li-Fraumeni syndrome. Many sarcomas are associated with specific somatic genetic alterations. For example, some specific subtypes are associated with gene translocations causing aberrant fusion proteins including Ewing sarcoma (EWS-FLI-1), synovial sarcoma (SSX-SYT), alveolar rhabdomyosarcoma (PAX3-FHKR), and myxoid liposarcomas (TLS-CHOP). These singular molecular alterations imply that some sarcomas are cytogenetically simple and may be more appropriate substrates for therapy targeted to a single molecular pathway. Sarcomas are commonly present as an asymptomatic mass or with local symptoms in an extremity or the retroperitoneum. Although tumor size, location, and histologic subtype have been implicated as prognostic factors in sarcomas, histologic grade remains the most important factor. Tumor grade is based on the degree of cellularity, differentiation, pleomorphism, necrosis, and the number of mitoses. Approximately 50-60% of patients with high grade soft tissue sarcoma will eventually have metastatic disease, as compared to 5-10% of patients with low grade disease. Sarcomas spread hematogenously with the most common site of spread being the lung, followed by liver, bone, and brain. About 50% of patients with sarcoma eventually expire due to locally advanced or metastatic disease with a median survival of 8-12 months.

Official Title
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Phase II Trial of Cetuximab in Patients With Metastatic and/or Locally Advanced Soft Tissue and Bony Sarcomas

Conditions
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Sarcoma

Intervention / Treatment
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* Drug: Cetuximab
* Drug: Cetuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for the study, patients must fulfill all of the following criteria: Patients must have the ability to give informed consent and have signed an approved informed consent form. Patients must have a pathologic diagnosis of soft tissue sarcoma or bony sarcoma. Patients with tumor tissue available for assessment of EGFR status performed by immunohistochemistry (IHC). Patients with Zubrod performance status 0-2. Patients must be 16 years of age or older. Patients, 16 years or older, must either be not of child bearing potential or have a negative pregnancy test within 7 days of treatment. Patients are considered not of child bearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal. If patients are childbearing or have child-fathering potential, they must use barrier contraception during intercourse while being treated on this study. Bone marrow function: absolute neutrophil count (ANC) 1,000/ul; platelets 75,000/l. Renal function: creatinine 2.0 x institutional upper limit of normal (ULN). Hepatic function: bilirubin 2.5 x ULN; AST 5.0 x ULN. Patients must have received at least one systemic chemotherapy treatment or else refuse to be treated with cytotoxic therapy. Twenty-eight days or more should have elapsed since the patient has received any prior systemic therapy. Patients must have documented symptomatic or radiologic progression to their preceding therapy. For patients treated with prior radiation, 21 days or more should have elapsed since the administration of the last fraction of radiation therapy and patients must have recovered from all associated toxicities. Patients must have measurable disease. The measurable lesion should be outside previously irradiated fields or have documented progression at least 6 weeks after completion of radiation. Exclusion Criteria: Any of the following criteria will make the patient ineligible to participate in this study: Acute hepatitis or known HIV. Active or uncontrolled infection. Significant history of uncontrolled cardiac disease i.e., uncontrolled hypertension, unstable angina, recent myocardial infarction (within prior 6 months), uncontrolled congestive heart failure, and cardiomyopathy with decreased ejection fraction. Prior therapy which specifically and directly targets the EGFR pathway. Prior severe infusion reaction to a monoclonal antibody. Any concurrent chemotherapy not indicated in the study protocol or any other investigational agent(s). Other active systemic malignancy within the past year.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: EGFR positive<br>The EGFR positive group will be conducted in a 2-stage minimax trial design to determine the rate of four-month progression free survival in this patient population treated with cetuximab | Drug: Cetuximab<br>* The initial dose of cetuximab is 400 mg/m2 intravenously administered over 120 minutes, followed by weekly infusions at 250 mg/m2 IV over 60 minutes.<br>|
| Active Comparator: EGFR Negative<br>The EGFR negative group will help us explore the possibility of benefit of cetuximab in a patient whose tumor does not express or minimally expresses EGFR. If benefit in progression-free survival or in another surrogate such as tumor response or a molecular event is seen in this group it would provide rationale to study this group further in subsequent trials | Drug: Cetuximab<br>* Cetuximab 400 mg/m2 over 120 min IV initial does followed by weekly Cetuximab 250 mg/m2 over 60 min<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Sarcoma Who Are Tumor Progression Free and Alive at Four Months From Start of Treatment With Single-agent Cetuximab. | Time of cetuximab administration to clinically documented progression of disease or death assessed for four months after starting cetuximab therapy | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival. | Time of cetuximab administration to clinically documented progression of disease or death assessed for four months | survival | 
| Overall Survival | Time of cetuximab administration to clinically documented death assessed for four months | months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Unresectable/metastatic high grade soft tissue bony sarcoma