Cetuximab, Cisplatin, and Radiation Therapy in Treating Patients With Stage IB, Stage II, Stage III, or Stage IVA Cervical Cancer

Study Overview
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Brief Summary
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This phase I trial is studying the side effects and best dose of cetuximab when given together with cisplatin and radiation therapy in treating patients with stage IB, stage II, stage III, or stage IVA cervical cancer. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as cisplatin, 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 and other types of radiation to kill tumor cells. Internal radiation therapy uses radioactive material placed directly into or near a tumor to kill tumor cells. Giving cetuximab together with cisplatin and radiation therapy may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose or safe biologically effective dose of cetuximab when administered in combination with cisplatin, external beam radiotherapy, and brachytherapy in patients with stage IB-IVA cervical cancer. II. Determine the feasibility of this regimen, in terms of chronic and acute toxic effects, in these patients. SECONDARY OBJECTIVES: I. Determine the distribution of progression-free survival and overall survival of patients treated with this regimen at 1 year after study entry. II. Determine the site of recurrence (locoregional vs distant) in patients treated with this regimen up to 1 year after study entry. III. Correlate response or progression-free survival with epidermal growth factor receptor expression in tumor samples from patients treated with this regimen at 1 year after study entry. IV. Correlate response or progression-free survival with grade of cetuximab-induced rash in patients treated with this regimen at 1 year after study entry. OUTLINE: This is a multicenter, dose-escalation study of cetuximab. Patients are stratified according to nodal status (positive para-aortic and/or pelvic lymph nodes vs negative para-aortic and pelvic lymph nodes). Patients receive cetuximab IV over 1-2 hours and cisplatin IV on days 1, 8, 15, 22, 29, and 36 (weeks 1-6). Patients also undergo external beam radiotherapy to the para-aortic and pelvic lymph nodes OR whole pelvis once daily on days 1-5, 8-12, 15-19, 22-26, and 29-33 (weeks 1-5). Patients then receive either 1 or 2 applications of low-dose rate brachytherapy in weeks 6-8 OR 5 applications of high-dose rate (HDR)* brachytherapy once weekly in weeks 4-8. Treatment continues in the absence of disease progression or unacceptable toxicity. NOTE: *No external beam radiotherapy is administered on the day of HDR brachytherapy. If the majority of external beam radiotherapy has been administered, HDR brachytherapy may be administered in 2 applications per week (separated by at least 72 hours) in order to complete all treatment within 8 weeks. Cohorts of 3-6 patients per stratum receive escalating doses of cetuximab until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. After completion of study treatment, patients are followed every 3 months for 1 year.

Official Title
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A Phase I Trial of Tailored Radiation Therapy With Concomitant Cetuximab (C225, NSC #714692) and Cisplatin (NSC #119875) in the Treatment of Patients With Cervical Cancer

Conditions
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Cervical Adenocarcinoma, Cervical Adenosquamous Carcinoma, Cervical Small Cell Carcinoma, Cervical Squamous Cell Carcinoma, Stage IB Cervical Cancer, Stage IIA Cervical Cancer, Stage IIB Cervical Cancer, Stage III Cervical Cancer, Stage IVA Cervical Cancer

Intervention / Treatment
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* Radiation: Internal Radiation Therapy
* Radiation: 3-Dimensional Conformal Radiation Therapy
* Biological: Cetuximab
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed cervical cancer Clinical stage IB-IVA disease Any cell type allowed Positive or negative pelvic and/or para-aortic lymph nodes by radiography Unstained sections from primary tumor available Performance status - GOG 0-1 Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Bilirubin ≤ 1.5 times upper limit of normal (ULN) SGOT ≤ 2.5 times ULN Alkaline phosphatase ≤ 2.5 times ULN Creatinine normal Creatinine clearance > 50 mL/min Patients with ureteral obstruction must undergo stent or nephrostomy tube placement prior to study entry No renal abnormality (e.g., pelvic kidney or horseshoe kidney) that would require modification of radiation fields No significant cardiac disease within the past 6 months, including any of the following: Uncontrolled hypertension Unstable angina Congestive heart failure Uncontrolled arrhythmia Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No sensory or motor neuropathy > grade 1 No septicemia No severe infection No circumstance that would preclude study participation or follow-up No other invasive malignancy within the past 5 years except nonmelanoma skin cancer No uncontrolled seizure disorder No active neurologic disease No history of active collagen vascular disease No prior chimerized or murine monoclonal antibody therapy No prior cytotoxic chemotherapy for cervical cancer No prior pelvic or abdominal radiotherapy for cervical cancer No concurrent intensity modulated radiotherapy No prior renal transplantation More than 30 days since prior major surgery (excluding diagnostic biopsy) No other prior therapy for cervical cancer No prior cancer treatment that would preclude study therapy No other concurrent investigational agents

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (brachytherapy, radiation, cetuximab, cisplatin)<br>Patients receive cetuximab IV over 1-2 hours and cisplatin IV on days 1, 8, 15, 22, 29, and 36 (weeks 1-6). Patients also undergo external beam radiotherapy to the para-aortic and pelvic lymph nodes OR whole pelvis once daily on days 1-5, 8-12, 15-19, 22-26, and 29-33 (weeks 1-5). Patients then receive either 1 or 2 applications of low-dose rate brachytherapy in weeks 6-8 OR 5 applications of high-dose rate (HDR)* brachytherapy once weekly in weeks 4-8. Treatment continues in the absence of disease progression or unacceptable toxicity. | Radiation: Internal Radiation Therapy<br> <br> * Other names: Radiation Brachytherapy;Radiation: 3-Dimensional Conformal Radiation Therapy<br> <br> * Other names: Radiation Conformal Therapy;Biological: Cetuximab<br>* Given IV<br>* Other names: IMC-C225;Drug: Cisplatin<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) or biologically effective dose (BED) of Cetuximab in combination with cisplatin and extended field radiation or whole pelvis radiation, graded using Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) | Evaluation of the regimens will be conducted separately by the type of radiation received (extended field radiation or whole pelvis radiation). | 6 weeks | 
| Incidence of toxicities at the MTD, assessed by CTCAE v3.0 |  | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  | From study entry until disease progression, death or date of last contact, up to 1 year | 
| Site of recurrence, loco-regional vs distant, assessed by clinical and radiological evaluation |  | From study entry until disease progression, death or date of last contact, up to 1 year | 
| Frequency of chronic toxicities, assessed by CTCAE v3.0 |  | From study entry until disease progression, death or date of last contact, up to 1 year |