Combination Chemotherapy and Cetuximab in Treating Patients With Metastatic Esophageal Cancer or Gastroesophageal Junction Cancer - Full Text View

Sponsors and Collaborators:	Cancer and Leukemia Group B National Cancer Institute (NCI) Eastern Cooperative Oncology Group
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00381706

Purpose

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.

Condition	Intervention	Phase
Esophageal Cancer	Drug: cetuximab Drug: cisplatin Drug: epirubicin hydrochloride Drug: fluorouracil Drug: irinotecan hydrochloride Drug: leucovorin calcium Drug: oxaliplatin	Phase II

MedlinePlus related topics: Cancer Esophageal Cancer Esophagus Disorders

Drug Information available for: Leucovorin Calcium Citrovorum factor Folinic acid calcium salt pentahydrate Leucovorin Cisplatin Irinotecan Irinotecan hydrochloride Fluorouracil Epirubicin hydrochloride Epirubicin Oxaliplatin Calcium gluconate Cetuximab

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized
Official Title:	Randomized Phase II Study of ECF-C, IC-C, or FOLFOX-C in Metastatic Esophageal and GE Junction Cancer

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Tumor response rate (complete and partial) in patients with measurable esophageal or GE junction adenocarcinoma [ Designated as safety issue: No ]
Tumor response rate (complete and partial) in patients with adenocarcinoma who have received at least 1 treatment course as measured by RECIST criteria [ Designated as safety issue: No ]

Secondary Outcome Measures:

Tumor response rate (complete and partial) in patients with squamous cell carcinoma [ Designated as safety issue: No ]
Overall survival [ Designated as safety issue: No ]
Progression-free survival [ Designated as safety issue: No ]
Time to treatment failure [ Designated as safety issue: No ]

Estimated Enrollment:	270
Study Start Date:	September 2006
Estimated Primary Completion Date:	July 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Arm I (ECF + cetuximab): Experimental Patients receive cetuximab IV over 1-2 hours on days 1, 8, and 15; epirubicin hydrochloride IV followed by cisplatin IV over 1 hour on day 1; and fluorouracil IV continuously on days 1-21. Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity.	Drug: cetuximab given IV Drug: cisplatin given IV Drug: epirubicin hydrochloride given IV
Arm II (IC + cetuximab): Experimental Patients receive cetuximab IV over 1-2 hours on days 1, 8, and 15 and cisplatin IV over 30 minutes followed by irinotecan hydrochloride IV over 90 minutes on days 1 and 8. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.	Drug: cetuximab given IV Drug: cisplatin given IV Drug: irinotecan hydrochloride given IV
ARM III (FOLFOX + cetuximab): Experimental Patients receive cetuximab IV over 1-2 hours on days 1 and 8; oxaliplatin IV over 2 hours followed by leucovorin calcium IV over 2 hours on day 1; and fluorouracil IV continuously over 46-48 hours on days 1 and 2. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity.	Drug: cetuximab given IV Drug: fluorouracil given IV Drug: leucovorin calcium given IV Drug: oxaliplatin given IV

Detailed Description:

OBJECTIVES:

Primary

Compare the tumor response rate in patients with metastatic esophageal or gastroesophageal junction cancer treated with epirubicin hydrochloride, cisplatin, fluorouracil, and cetuximab (ECF-C); irinotecan hydrochloride, cisplatin, and cetuximab (IC-C); or fluorouracil, oxaliplatin, leucovorin calcium, and cetuximab (FOLFOX-C).

Secondary

Compare overall survival of patients treated with these regimens.
Compare progression-free survival of patients treated with these regimens.
Compare treatment failure in patients treated with these regimens.
Determine the type and severity of toxicities associated with these regimens in the multi-institutional phase II setting.
Correlate quantitative immunohistochemistry results with objective response rate, overall survival, and time to progression in these patients.
Evaluate the cellular damage (i.e., apoptosis) as a result of oxaliplatin in these patients.
Determine if germline epidermal growth factor receptor (EGFR) variants correlate with skin rash in patients treated with cetuximab.
Correlate germline EGFR variants with tumor EGFR expression as measured by immunohistochemistry.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to histology (squamous cell carcinoma vs adenocarcinoma) and ECOG performance status (0 or 1 vs 2). Patients are randomized to 1 of 3 treatment arms.

Arm I (ECF + cetuximab): Patients receive cetuximab IV over 1-2 hours on days 1, 8, and 15; epirubicin hydrochloride IV followed by cisplatin IV over 1 hour on day 1; and fluorouracil IV continuously on days 1-21. Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity.
Arm II (IC + cetuximab): Patients receive cetuximab IV over 1-2 hours on days 1, 8, and 15 and cisplatin IV over 30 minutes followed by irinotecan hydrochloride IV over 90 minutes on days 1 and 8. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
ARM III (FOLFOX + cetuximab): Patients receive cetuximab IV over 1-2 hours on days 1 and 8; oxaliplatin IV over 2 hours followed by leucovorin calcium IV over 2 hours on day 1; and fluorouracil IV continuously over 46-48 hours on days 1 and 2. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity.

Patients undergo tumor sample collection at baseline to examine quantitative immunofluorescence with subcellular localization for epidermal growth factor receptor (EGFR), phospho EGFR, HER-2, phospho-HER-2, HER-3, HER-4, FEF, AKT, phospho AKT, PTEN, gastrin-releasing peptide (GRP), and GRP receptor levels. Tumor samples are collected at baseline from patients randomized to arm III to evaluate molecular mechanisms for correlative studies. Cellular damage (i.e., apoptosis) by oxaliplatin is determined by DNA fragmentation by TUNEL assay.

After completion of study treatment, patients are followed periodically for up to 2 years.

PROJECTED ACCRUAL: A total of 270 patients will be accrued for this study.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically, cytologically, or radiologically confirmed esophageal cancer, including any of the following types:
- Squamous cell carcinoma
- Adenocarcinoma* of the esophagus
- Adenocarcinoma* of the gastroesophageal (GE) junction according to Siewert classification
  - Type I or II disease
    - No type III disease NOTE: Undifferentiated adenocarcinoma and adenosquamous tumor will be considered as adenocarcinoma
Metastatic disease or locally recurrent or residual (post-resection) disease
- Resected esophageal or GE junction disease that develops radiological or clinical evidence of metastatic disease does not require histological or cytological confirmation of metastatic disease unless 1 of the following is true:
  - More than 5 years since primary surgery and development of metastatic disease
  - Primary cancer was stage I
Measurable disease, defined as at least 1 unidimensionally measurable lesion (longest diameter) as ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan
Must have ≥ 1 paraffin block (or ≥ 15 unstained slides) available for analysis of tumor epidermal growth factor receptor (EGFR) status
No known CNS metastases or carcinomatous meningitis

PATIENT CHARACTERISTICS:

ECOG performance status 0-2
Platelet count ≥ 100,000/mm^3
Granulocyte count ≥ 1,500/mm^3
Creatinine ≤ 1.5 mg/dL
AST ≤ 5.0 times upper limit of normal
Bilirubin ≤ 1.5 mg/dL
Albumin ≥ 2.5 g/dL
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
Must have a stable weight loss of (i.e., < 1 pound weight loss during the past week)
No diarrhea ≥ grade 2 within the past 7 days
No myocardial infarction within the past 6 months
No New York Heart Association class III or IV congestive heart failure
No interstitial pneumonia or symptomatic interstitial fibrosis of the lung
No seizure disorder or active neurological disease requiring anti-epileptic medication
No peripheral neuropathy ≥ grade 2
No evidence of Gilbert's syndrome
No prior allergic reaction to chimerized or murine monoclonal antibody therapy or documented presence of human anti-mouse antibodies (HAMA)

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
No prior chemotherapy or radiotherapy
No prior therapy that specifically and directly targets the EGFR pathway
At least 4 weeks since prior major surgery* and recovered
At least 2 weeks since prior minor surgery* and recovered
No concurrent palliative radiotherapy
No other concurrent investigational agent
No other concurrent chemotherapy
No concurrent hormonal therapy except for the following:
- Steroids given temporarily for adrenal failure
- Hormones for nondisease-related conditions (e.g., insulin for diabetes)
- Intermittent steroids (e.g., dexamethasone) as an antiemetic NOTE: *Insertion of a vascular device is not considered major or minor surgery

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00381706

Show 243 Study Locations

Sponsors and Collaborators

Cancer and Leukemia Group B

National Cancer Institute (NCI)

Eastern Cooperative Oncology Group

Investigators

Study Chair:	Peter C. Enzinger, MD	Dana-Farber Cancer Institute
Investigator:	David H. Ilson, MD, PhD	Memorial Sloan-Kettering Cancer Center
Study Chair:	Barbara A. Burtness, MD	Fox Chase Cancer Center

More Information

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Study ID Numbers:	CDR0000505535, CALGB-80403, ECOG-E1206
Study First Received:	September 26, 2006
Last Updated:	January 15, 2009
ClinicalTrials.gov Identifier:	NCT00381706
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

squamous cell carcinoma of the esophagus
adenocarcinoma of the esophagus
stage IV esophageal cancer
recurrent esophageal cancer

Study placed in the following topic categories:

Gastrointestinal Diseases
Squamous cell carcinoma
Esophageal Neoplasms
Irinotecan
Leucovorin
Oxaliplatin
Cisplatin
Carcinoma, squamous cell
Esophageal neoplasm
Digestive System Neoplasms
Esophageal disorder
Cetuximab
Epirubicin

Recurrence
Camptothecin
Carcinoma
Epidermoid carcinoma
Calcium, Dietary
Digestive System Diseases
Head and Neck Neoplasms
Fluorouracil
Gastrointestinal Neoplasms
Esophageal Diseases
Adenocarcinoma
Carcinoma, Squamous Cell

Additional relevant MeSH terms:

Antimetabolites
Antimetabolites, Antineoplastic
Vitamin B Complex
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Antineoplastic Agents
Growth Substances
Physiological Effects of Drugs
Enzyme Inhibitors

Antibiotics, Antineoplastic
Immunosuppressive Agents
Pharmacologic Actions
Neoplasms
Neoplasms by Site
Vitamins
Therapeutic Uses
Micronutrients
Antineoplastic Agents, Phytogenic

ClinicalTrials.gov processed this record on January 16, 2009