Combination Chemotherapy and Cetuximab in Treating Patients With Metastatic Esophageal Cancer or Gastroesophageal Junction Cancer
Condition: Esophageal Cancer
MeSH terms: Esophageal Neoplasms
Intervention: cetuximab; ECF; IC; FOLFOX
Intervention description: given IV; epirubicin and 5-fluorouracil given IV; cisplatin and irinotecan given IV; oxaliplatin , leucovorin and 5-fluorouracil IV
Intervention MeSH terms: Leucovorin; Cisplatin; Fluorouracil; Oxaliplatin; Irinotecan; Cetuximab; Epirubicin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 245.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: squamous cell carcinoma of the esophagus; adenocarcinoma of the esophagus; stage IV esophageal cancer; recurrent esophageal cancer

Summary:

      RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor
      cells, either by killing the cells or by stopping them from dividing. 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. Giving more than one chemotherapy drug (combination chemotherapy)
      together with cetuximab may kill more tumor cells.

      PURPOSE: This randomized phase II trial is studying three different combination chemotherapy
      regimens to compare how well they work when given together with cetuximab in treating
      patients with metastatic esophageal cancer or gastroesophageal junction cancer.
    

Eligibility criteria:

        1. Metastatic disease of the esophagus or gastroesophageal junction

               1. Histologic, cytologic or radiologic documentation of metastatic squamous cell
                  carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction.
                  Radiologic, endoscopic, histologic or cytologic evidence of locally recurrent or
                  locally residual (post-resection) disease is also permitted.

               2. For the purposes of this study, undifferentiated adenocarcinomas and
                  adenosquamous tumors will be considered as adenocarcinomas. In addition, tumors
                  involving the gastroesophageal junction will be defined by the Siewert
                  classification.

               3. Patients with gastroesophageal junction tumors who are eligible:

                    -  AEG Type I: Adenocarcinoma of the distal esophagus which usually arises from
                       an area with specialized intestinal metaplasia of the esophagus (eg,
                       Barrett's esophagus, and may infiltrate the esophagogastric junction from
                       above).

                    -  AEG Type II: True carcinoma of the cardia arising from the cardiac
                       epithelium or short segments with intestinal metaplasia at the
                       esophagogastric junction.

               4. Patients with gastroesophageal junction tumors who are NOT eligible:

                    -  AEG Type III: Subcardial gastric carcinoma which infiltrates the
                       esophagogastric junction and distal esophagus from below.

          2. Patients must have at least one paraffin block available (or at least 15 unstained
             slides for analysis of tumor EGFR status.

               1. Patients with a history of esophageal and GE junction carcinoma treated by
                  surgical resection who develop radiological or clinical evidence of metastatic
                  cancer do not require separate histological or cytological confirmation of
                  metastatic disease unless an interval of greater than five years has elapsed
                  between the primary surgery and the development of metastatic disease OR the
                  primary cancer was stage I.

               2. Clinicians should consider biopsy of lesions to establish the diagnosis of
                  metastatic esophageal or GE junction carcinoma if there is substantial clinical
                  ambiguity regarding the nature or source of apparent metastases.

          3. Patients with Measurable Disease - Lesions that can be accurately measured in at least
             one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional
             techniques or as ≥ 10 mm with spiral CT scan.

          4. Prior Treatment:

               1. No prior chemotherapy or radiotherapy. No prior therapy which specifically and
                  directly targets the EGF(R) pathway.

               2. No prior allergic reaction to chimerized or murine monoclonal antibody therapy or
                  documented presence of human anti-mouse antibodies (HAMA).

               3. Patients must have completed any major surgery ≥ 4 weeks or any minor surgery ≥ 2
                  weeks before registration. Patients must have fully recovered from the procedure.
                  Insertion of a vascular access device is not considered major or minor surgery.

               4. No concurrent use of investigational agents is allowed while participating in
                  this study.

          5. Patient Characteristics:

               1. ECOG Performance Status of 0-2

               2. ≥ 18 years of age

               3. Patients must be documented to have a stable weight (or less than one pound
                  weight loss) for at least one week prior to registration.

               4. Non-pregnant and not breast-feeding. The effects of cetuximab, cisplatin,
                  epirubicin, fluorouracil, leucovorin, irinotecan, and oxaliplatin on a developing
                  human fetus are not well-known. Because the risk of toxicity in nursing infants
                  secondary to cetuximab, cisplatin, epirubicin, fluorouracil, irinotecan, and
                  oxaliplatin treatment of the mother is unknown but may be harmful, breastfeeding
                  must be discontinued.

          6. No myocardial infarction < 6 months prior to registration or New York Heart
             Association classification III or IV.

          7. No ≥ grade 2 diarrhea within 7 days prior to registration.

          8. Patients may not concurrently have any of the following conditions:

               1. Known central nervous system metastases or carcinomatous meningitis

               2. Interstitial pneumonia or symptomatic interstitial fibrosis of the lung

               3. Seizure disorder or active neurological disease requiring anti-epileptic
                  medication

               4. ≥ grade 2 peripheral neuropathy

          9. No evidence of Gilbert's Syndrome - Patients with Gilbert's Syndrome may have a
             greater risk of irinotecan toxicity due to the abnormal glucuronidation of SN-38, the
             active metabolite of irinotecan. Evidence of Gilbert's Syndrome would include
             documentation of elevation of indirect bilirubin at any time in the patient's medical
             history.

         10. Required Initial Laboratory Data:

               1. Granulocytes ≥ 1500/µl

               2. Platelet count ≥ 100,000/µl

               3. Creatinine ≤ 1.5 mg/dL

               4. AST (SGOT) ≤ 5.0 x Upper limits of normal

               5. Total bilirubin ≤ 1.5 mg/dL

               6. Albumin ≥ 2.5 grams/dL