RATIONALE: 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.

PURPOSE: 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.

Condition	Treatment or Intervention	Phase
Cervical Cancer	Drug: cetuximab  Drug: cisplatin  Procedure: anti-cytokine therapy  Procedure: antiangiogenesis therapy  Procedure: antibody therapy  Procedure: biological response modifier therapy  Procedure: brachytherapy  Procedure: chemosensitization/potentiation  Procedure: chemotherapy  Procedure: growth factor antagonist therapy  Procedure: monoclonal antibody therapy  Procedure: radiation therapy  Procedure: radiosensitization	Phase I

Further Study Details: 

OBJECTIVES: Primary

• 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.
• Determine the feasibility of this regimen, in terms of chronic and acute toxic effects, in these patients.

Secondary

• Determine the distribution of progression-free survival and overall survival of patients treated with this regimen.
• Determine the site of recurrence (locoregional vs distant) in patients treated with this regimen.
• Correlate response or progression-free survival with epidermal growth factor receptor expression in tumor samples from patients treated with this regimen.
• Correlate response or progression-free survival with grade of cetuximab-induced rash in patients treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of cetuximab. Patients are stratified according to nodal status (positive peri-aortic and/or pelvic lymph nodes vs negative peri-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 peri-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.

PROJECTED ACCRUAL: Approximately 30-100 patients will be accrued for this study.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed cervical cancer
• Clinical stage IB-IVA disease
• Any cell type allowed
• Positive or negative pelvic and/or peri-aortic lymph nodes by radiography
• Unstained sections from primary tumor available

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• GOG 0-1

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• SGOT ≤ 2.5 times ULN
• Alkaline phosphatase ≤ 2.5 times ULN

Renal

• Creatinine normal OR
• 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

Cardiovascular

• No significant cardiac disease within the past 6 months, including any of the following:
• Uncontrolled hypertension
• Unstable angina
• Congestive heart failure
• Uncontrolled arrhythmia

Other

• 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

PRIOR CONCURRENT THERAPY: Biologic therapy

• No prior chimerized or murine monoclonal antibody therapy

Chemotherapy

• No prior cytotoxic chemotherapy for cervical cancer

Endocrine therapy

• Not specified

Radiotherapy

• No prior pelvic or abdominal radiotherapy for cervical cancer
• No concurrent intensity modulated radiotherapy

Surgery

• No prior renal transplantation
• More than 30 days since prior major surgery (excluding diagnostic biopsy)

Other

• No other prior therapy for cervical cancer
• No prior cancer treatment that would preclude study therapy
• No other concurrent investigational agents

Study chairs or principal investigators

John H. Farley, MD,  Study Chair,  Tripler Army Medical Center   
Russell J. Schilder, MD,  Fox Chase Cancer Center   

Study ID Numbers:  CDR0000413880; GOG-9918; NCT00104910
Record last reviewed:  February 2005
Last Updated:  March 15, 2005
Record first received:  March 3, 2005
ClinicalTrials.gov Identifier:  NCT00104910
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08