Paclitaxel, Cisplatin, and Radiation Therapy With or Without Cetuximab in Treating Patients With Locally Advanced Esophageal Cancer

OBJECTIVES:

Primary

- To evaluate whether the addition of cetuximab to chemotherapy comprising paclitaxel,
cisplatin, and radiotherapy improves overall survival compared with paclitaxel,
cisplatin, and radiotherapy alone in patients with esophageal cancer treated without
surgery.

Secondary

- To evaluate whether the addition of cetuximab to paclitaxel, cisplatin, and radiotherapy
improves local control by increasing the clinical complete response and decreasing local
recurrence in these patients.

- To evaluate adverse events in these patients.

- To evaluate endoscopic complete response rates in these patients.

- To evaluate if the addition of cetuximab to paclitaxel, cisplatin, and radiotherapy
improves the Esophageal Cancer Subscale (ECS) score of the Functional Assessment of
Cancer Therapy - Esophagus (FACT-E) quality of life tool.

- To evaluate the quality-adjusted survival of each treatment arm using EQ-5D if the
primary endpoint supports the primary hypothesis.

OUTLINE: This is a multicenter study. Patients are stratified according to histology
(adenocarcinoma vs squamous), cancer lesion size (< 5 cm vs ≥ 5 cm), and disease status of
celiac nodes (present vs absent). Patients are randomized to 1 of 2 treatment arms.

Inclusion Criteria:

1. Pathologically (histologic or cytologic) proven diagnosis of primary squamous cell or
adenocarcinoma of the esophagus or gastroesophageal junction within 12 weeks prior to
registration. Patients with involvement of the gastroesophageal junction with Siewert
type I or II tumors (tumors arising from the distal esophagus and involving the
esophagogastric junction or tumors starting at the esophagogastric junction and
involving the cardia) are eligible.

- 1.1 Disease must be encompassed in a radiotherapy field.

- 1.2 Patients with celiac, perigastric, mediastinal or supraclavicular adenopathy
are eligible.

- 1.3 Patients with cervical esophageal carcinoma are eligible.

2. Stage T1N1M0; T2-4, Any N, M0; Any T, Any N, M1a, based upon the following minimum
diagnostic work-up:

- 2.1 History/physical examination within 6 weeks prior to registration

- 2.2 Positron emission tomography (PET)/positron emission tomography-computed
tomography (PET-CT) scan (strongly recommended) or chest/abdominal CT within 6
weeks prior to registration

- 2.3 Electrocardiogram (EKG) within 6 weeks of study entry

- 2.4 Endoscopy with biopsy or cytology by fine needle aspiration (FNA) (must be
able to document histologic subtype) within 12 weeks of study entry. Patients
with T3-4 proximal thoracic esophageal tumors (15-25 cm) must undergo
bronchoscopy to exclude fistula. (NOTE: Any images from endoscopic procedures up
to the time of progression must be kept in the patient's confidential study
file.)

3. Zubrod performance status 0-2

4. Age ≥ 18 and ≤ 74 (upper limit was set at 74 in an amendment)

5. Complete blood count (CBC)/differential obtained within 2 weeks prior to registration
on study, with adequate bone marrow function defined as follows:

- 5.1 Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3

- 5.2 Platelets ≥ 100,000 cells/mm3

- 5.3 Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to
achieve Hgb ≥8.0 g/dl is acceptable.)

6. Additional laboratory studies obtained within 2 weeks prior to registration on study

- 6.1 Creatinine ≤ 1.5 mg/dl

- 6.2 Bilirubin ≤ 1.5 x upper limit of normal

- 6.3 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3 x
upper limit of normal

- 6.4 Serum pregnancy test for women of childbearing potential

7. Patient's total intake (oral/enteral) must be ≥ 1500 kCal/day

8. Patient must provide study-specific informed consent prior to study entry

9. Women of childbearing potential and male participants must practice adequate
contraception

Exclusion Criteria:

1. Evidence of tracheoesophageal fistula, or invasion into the trachea or major bronchi.
Patients with T3-4 proximal thoracic esophageal tumors (15-25 cm) must undergo
bronchoscopy to exclude fistula.

2. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 2 years (For example, carcinoma in situ of the breast, oral cavity,
or cervix are all permissible).

3. Prior systemic chemotherapy for esophageal cancer; note that prior chemotherapy for a
different cancer is allowable.

4. Prior radiation therapy that would result in overlap of planned radiation therapy
fields.

5. Prior therapy that specifically and directly targets the epidermal growth factor
receptor (EGFR) pathway.

6. Prior platinum-based and/or paclitaxel-based therapy.

7. Prior allergic reaction to the study drugs involved in this protocol.

8. Prior severe infusion reaction to a monoclonal antibody.

9. Severe, active comorbidity, defined as follows:

- 9.1 Unstable angina and/or congestive heart failure requiring hospitalization
within the last 3 months

- 9.2 Transmural myocardial infarction within the last 6 months

- 9.3 Acute bacterial or fungal infection requiring intravenous antibiotics at the
time of registration

- 9.4 Chronic obstructive pulmonary disease exacerbation or other respiratory
illness requiring hospitalization or precluding study therapy at the time of
registration

- 9.5 Acquired immune deficiency syndrome (AIDS) based upon current Centers for
Disease Control and Prevention (CDC) definition; note, however, that human
immunodeficiency virus (HIV) testing is not required for entry into this
protocol. The need to exclude patients with AIDS from this protocol is necessary
because the treatments involved in this protocol may be significantly
immunosuppressive. Protocol-specific requirements may also exclude
immunocompromised patients.

10. Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception; this exclusion is
necessary because the treatment involved in this study may be significantly
teratogenic.

11. Women who are nursing.