Use of Cetuximab for Unresectable or Metastatic Esophageal and Gastric Cancer

Phase 2

Completed

Brief Summary: Purpose: There remains a great need for novel therapeutic agents and treatment strategies for advanced esophagogastric cancer. Preclinical and clinical studies have demonstrated increased EGFR expression in a significant proportion of both esophageal and gastric carcinomas. Inactivation of EGFR through use of a monoclonal antibody in preclinical models has resulted in inhibition of tumor growth. Agents designed to block the EGFR pathway have demonstrated disease control among previously treated patients with metastatic esophageal and gastric cancer. The proposed mechanism of action for cetuximab is its ability to effectively disrupt EGFR-mediated signal transduction pathways that ultimately leads to halting cell cycle progression, induces apoptosis, and also inhibits processes important for tumor growth, such as cell invasion and angiogenesis.

Detailed Description: OBJECTIVES:

Primary - To assess the response rate of single-agent cetuximab in patients with advanced esophageal or gastric cancer who have failed 1-2 prior chemotherapy regimens given in the metastatic setting.

Secondary

* To evaluate the duration of response, progression-free survival and overall survival.

* To assess the safety of cetuximab.

Exploratory

- To assess whether levels of EGFR expression and/or EGFR mutation status correlates with response and toxicity of cetuximab.

STATISTICAL DESIGN:

This study used a two-stage design to evaluate efficacy of cetuximab based on overall response (OR) defined as complete response (CR) or partial response (PR). The null and alternative OR rate were 5% and 15%. If one or more patients enrolled in the stage one cohort (n=20 patients) achieved PR or better than accrual would proceed to stage two (n=16 patients). There was 36% probability of stopping the trial at stage one if the true OR rate was 5%. The probability that the regimen would be considered promising if the true OR rate was 5% was 10% and 80% if the true OR rate was 15%.

Recruitment & Eligibility

Inclusion Criteria

Histologically confirmed, unresectable or metastatic stage IV esophageal or gastric adenocarcinoma. Tumors with squamous cell differentiation, including those with a mixture of squamous and adenomatous differentiation, are excluded.
Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, greater than or equal to 1 cm (longest diameter) by spiral computed tomography (CT) scan or greater than or equal to 2 cm by other radiographic technique. Disease in an irradiated field as only site of measurable disease is acceptable if there has been a clear progression of the lesion.
Patients must have at least one paraffin block or twenty unstained slides available for analysis of epidermal growth factor receptor (EGFR) status.
Treatment with 1-2 prior chemotherapy regimens given in the metastatic setting for unresectable or metastatic esophageal or gastric carcinoma.
ECOG performance status 0-2.
Life expectancy greater or equal to 12 weeks.
Age 18 years or older.
Ability to sign an informed consent document.
Neutrophils greater than or equal to 1,000/mm3.
Platelets greater than or equal to 75,000/mm3.
Serum bilirubin less than or equal to 2.0 mg/dl.
Serum creatinine less than or equal to 1.5 mg/dl.
Aspartate aminotransferase (AST or SGOT) less than or equal to 2.5 x upper institutional normal limit.

Exclusion Criteria

Pregnant or lactating women. Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days of initiation of therapy. Men and women of reproductive potential may not participate unless they have agreed to use an effective contraceptive method while in this study.
Subjects should have no other active malignancy other than non-melanoma skin cancer or in-situ cervical carcinoma. A resected cancer (other than in-situ carcinoma) must have demonstrated no evidence of recurrence for at least 3 years.
Subjects should not have a significant history of cardiac disease, i.e., uncontrolled hypertension; unstable angina; congestive heart failure; myocardial infarction less than 6 months prior to registration; or serious uncontrolled cardiac arrhythmia.
Subjects must not have received prior cetuximab or other therapy that specifically and directly targets the EGFR pathway. Prior therapy with bevacizumab is permissible.
Subjects must not have experienced prior severe infusion reaction to a monoclonal antibody.
Subjects must not have received any chemotherapy regimen or radiation therapy within 28 days prior to study entry.
Patients must have completed any major surgery 4 weeks or any minor surgery 2 weeks prior to the first infusion of cetuximab. Patients must have fully recovered from the procedure.
No concurrent use of chemotherapy, radiation, or other investigational agents is allowed while participating in this study.

Arm && Interventions

Group	Intervention	Description
Cetuximab	Cetuximab	Patients received cetuximab at an initial dose of 400 mg/m2 administered IV over 120 min, followed by weekly infusions at 250 mg/m2 administered IV over 60 min. Once cycle was 4 weeks of therapy. Patients received treatment until disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Overall Response Rate	Disease was evaluated radiologically at baseline and every 2 cycles on treatment; Treatment continued until disease progression or unacceptable toxicity. Treatment duration was a median of 6 weeks (range 1-23 weeks).	Overall response (OR) rate was defined as achieving partial response (PR) or complete response (CR) based on RECIST 1.0 criteria on treatment. Per RECIST 1.0 for target lesions, CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. To be assigned a status of CR or PR, changes in tumor measurements must be confirmed by repeat assessments performed no fewer than 4 weeks after the response criteria are first met. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.

Secondary Outcome Measures

Name	Time	Method

Locations (4): Massachusetts General Hospital
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Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
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Boston, Massachusetts, United States
Dana-Farber Cancer Institute
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Boston, Massachusetts, United States
North Shore Medical Center Cancer Center
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Peabody, Massachusetts, United States