S0414 Cetuximab, Combo Chemo, and RT in Locally Advanced Esophageal Cancer

Study Overview
=================
Brief Summary
-----------------
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. Cetuximab may also stop the growth of esophageal cancer by blocking blood flow to the tumor and by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cisplatin and irinotecan, 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 to kill tumor cells. Giving cetuximab together with combination chemotherapy and radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving cetuximab together with combination chemotherapy and radiation therapy works in treating patients with locally advanced esophageal cancer that cannot be removed by surgery.

Detailed Description
-----------------
OBJECTIVES: Primary Determine the 2-year overall survival of patients with previously untreated, clinically unresectable, locally advanced squamous cell carcinoma or adenocarcinoma of the esophagus treated with cetuximab, cisplatin, irinotecan, and thoracic radiotherapy. Secondary Determine the toxicity profile of this regimen in these patients. Determine the probability of objective response (confirmed and unconfirmed, complete and partial) in patients with measurable disease treated with this regimen. Determine the time to progression in patients with measurable disease treated with this regimen. Correlate, preliminarily, gene expression (RNA) levels and germline polymorphisms of genes involved in DNA repair (e.g., ECRCC-1 and XRCC-1), drug metabolism (e.g., UGT1A1), and the epidermal growth factor receptor (EGFR) pathway (e.g., EGFR, interleukin-8, and vascular endothelial growth factor) with response, time to progression, overall survival, and toxicity in patients treated with this regimen. (This will not be completed as this study was closed due to poor accrual.) OUTLINE: This is a multicenter study. Patients receive cetuximab intravenous (IV) over 1-2 hours on days 1, 8, and 15. Patients also receive cisplatin IV and irinotecan IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Beginning on day 1 of course 3, patients undergo thoracic radiotherapy once daily 5 days a week for 5-6 weeks (total of 28 treatments). After completion of study treatment, patients are followed at 4 weeks and then every 3-6 months for up to 5 years after study entry. PROJECTED ACCRUAL: A total of 75-100 patients (75 with adenocarcinoma and 25 with squamous cell carcinoma) will be accrued for this study.

Official Title
-----------------
Cetuximab Plus Cisplatin, Irinotecan and Thoracic Radiotherapy (TRT) for Locally Advanced (Non-Metastatic), Clinically Unresectable Esophageal Cancer: A Phase II Trial With Molecular Correlates

Conditions
-----------------
Esophageal Cancer

Intervention / Treatment
-----------------
* Biological: cetuximab
* Drug: cisplatin
* Drug: irinotecan hydrochloride
* Radiation: radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed primary squamous cell carcinoma or adenocarcinoma of the thoracic esophagus (≥ 20 cm from the incisors*) or the gastroesophageal junction (confined to ≤ 2 cm into the gastric cardia) Disease confined to the esophagus or peri-esophageal soft tissue T4, M0 disease Surgically unresectable disease by esophageal endoscopic ultrasonography OR medically unresectable disease NOTE: *Patients with primary disease < 26 cm from the incisors must undergo bronchoscopy AND have negative cytology within the past 4 weeks Measurable or non-measurable disease by x-ray, CT scan and/or MRI, or physical examination within the past 4 weeks (for measurable disease) or within the past 6 weeks (for non-measurable disease) Tumor specimens available No recurrent disease PATIENT CHARACTERISTICS: Age 18 and over Performance status Zubrod 0-2 Life expectancy Not specified Hematopoietic Absolute neutrophil count (ANC) ≥ 1,500/mm^3 White Blood Cell (WBC) count ≥ 3,000/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 10.0 g/dL Hepatic Albumin normal Bilirubin normal Alkaline phosphatase normal Serum glutamic oxaloacetic transaminase (SGOT) or Serum glutamic pyruvic transaminase (SGPT) ≤ 2.5 times upper limit of normal Renal Creatinine clearance > 50 mL/min Other Not pregnant or nursing Fertile patients must use effective contraception No prior severe reaction to monoclonal antibodies No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy No prior chemotherapy for esophageal cancer Endocrine therapy Not specified Radiotherapy No prior radiotherapy for esophageal cancer No concurrent intensity modulated radiotherapy No concurrent cobalt-60 Surgery No prior surgical resection or attempted surgical resection of esophageal cancer

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Cetuximab+Cisplatin+Irinotecan followed by radiation therapy (RT) in Cycle 3. | Biological: cetuximab<br>* 400mg/m^2 loading dose, intravenous (IV) over 120 min, day 1 of cycle 1 only. 250mg/m^2 maintenance dose, IV over 60 min, Days 8 & 15 of Cycle 1 and Days 1, 8, and 15 of subsequent cycles.<br>* Other names: Erbitux;Drug: cisplatin<br>* 30mg/m^2, bolus intravenous (IV), on Days 1 & 8 of each cycle.<br>* Other names: Platinol;Drug: irinotecan hydrochloride<br>* 65mg/m^2, intravenous (IV) over 30 min, on Days 1 & 8 of each cycle.<br>* Other names: CPT-11;Radiation: radiation therapy<br>* The total dose to the prescription point will be 5,040 cGy given in 28 fractions. The patient will be treated with one fraction per day with all fields treated per day. 180 cGy will be delivered to the isocenter. The dose variation in the planning target volume (PTV) will be +7% and -5% of the prescription point dose.<br>* Other names: TRT;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival at 2 Years | Measured from time of registration to date of death due to any cause, or last contact date | 0-2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal. | Patients were assessed for adverse events after every two cycles of chemotherapy. | 
| Objective Response (Confirmed and Unconfined, Complete and Partial) | Complete response (CR) is complete disappearance of all measurable and non-measurable disease. No new lesions. No disease related symptoms. Normalization of markers and other abnormal lab values. Partial response (PR) applies only to patients with at least one measurable lesion. Greater than or equal to 30% decrease under baseline of the sum of longest diameters of all target measurable lesions. No unequivocal progression of non-measurable disease. No new lesions. Confirmation of CR or PR means a repeat scan at least 4 weeks apart documented before progression or symptomatic deterioration. | at week 16, then every 3 months until progression | 
| Progression Free Survival | Measured from date of registration to date of first observation of progression or symptomatic deterioration. Patients last known to be alive and progression-free are censored at date of last contact. | 0 - 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
squamous cell carcinoma of the esophagus, stage III esophageal cancer, adenocarcinoma of the esophagus