Radiation Therapy, Paclitaxel, and Carboplatin With or Without Trastuzumab in Treating Patients With Esophageal Cancer

PRIMARY OBJECTIVES:

l. To determine if trastuzumab increases disease-free survival when combined with trimodality
treatment (radiation plus chemotherapy followed by surgery) for patients with human epidermal
growth factor receptor 2 (HER2)-overexpressing esophageal adenocarcinoma.

SECONDARY OBJECTIVES:

I. To evaluate if the addition of trastuzumab to trimodality treatment increases the
pathologic complete response rate and overall survival for patients with HER2-overexpressing
esophageal adenocarcinoma.

II. To develop a tissue bank of tumor tissue from patients with non-metastatic esophageal
adenocarcinoma.

III. To determine molecular correlates of complete pathologic response, disease-free
survival, and overall survival for patients with HER2-overexpressing esophageal
adenocarcinoma treated with neoadjuvant and maintenance trastuzumab.

IV. To evaluate predictors of cardiotoxicity in patients with esophageal cancer treated with
trastuzumab and chemoradiation.

V. To evaluate adverse events associated with the addition of trastuzumab to trimodality
treatment for patients with non-metastatic esophageal adenocarcinoma.

PATIENT-REPORTED QUALITY OF LIFE OBJECTIVES:

I. To determine if the addition of trastuzumab to trimodality treatment improves the
patient-reported Functional Assessment of Cancer Therapy for Esophageal Cancer (FACT-E)
Esophageal Cancer Subscale (ECS) score.

II. To determine if an improvement in the FACT-E ECS score at 6-8 weeks post completion of
neoadjuvant chemoradiation correlates with pathologic complete response.

III. To determine if pathologic complete response correlates with the FACT-E ECS score at 1
year and/or 2 years from the start of chemoradiation.

IV. To determine if the addition of trastuzumab to trimodality treatment improves the Swallow
Index and Eating Index Subscale scores of the FACT-E.

V. To determine if the addition of trastuzumab to paclitaxel, carboplatin, and radiation
impacts quality-adjusted survival.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo radiotherapy once daily 5 days a week for 5.5 weeks. Patients also
receive trastuzumab intravenously (IV) over 30-90 minutes on days 1, 8, 15, 22, 29, 36, and
57 and paclitaxel IV over 60 minutes and carboplatin IV over 30-60 minutes on days 1, 8, 15,
22, 29, and 36. Beginning 21-56 days after surgery, patients receive trastuzumab IV over
30-90 minutes. Treatment repeats every 21 days for 13 courses in the absence of disease
progression or unacceptable toxicity.

ARM II: Patients undergo radiotherapy once daily 5 days a week for 5.5 weeks. Patients also
receive paclitaxel IV over 60 minutes and carboplatin IV over 30-60 minutes on days 1, 8, 15,
22, 29, and 36.

Within 5-8 weeks after completion of radiotherapy, all patients undergo surgery.

After completion of study therapy, patients are followed up every 4 months for 2 years and
then yearly thereafter.

Inclusion Criteria:

- Pathologically confirmed primary adenocarcinoma of the esophagus that involves the mid
(up to 25 cm), distal, or esophagogastric junction; the cancer may involve the stomach
up to 5 cm

- Endoscopy with biopsy

- PRIOR TO STEP 1 REGISTRATION BUT WITHIN 56 DAYS PRIOR TO STEP 2 REGISTRATION

- Intent to submit tissue for central HER2 testing

- Stage T1N1-2, T2-3N0-2, according to the American Joint Committee on Cancer (AJCC) 7th
edition staging, based on the following minimum diagnostic work-up:

- Chest/abdominal/pelvic computed tomography (CT) or whole-body positron emission
tomography (PET)/CT (NOTE: if CT is performed at this time point, whole-body
PET/CT will be required prior to step 2 registration; PET/CT of skull base to
mid-thigh is acceptable) (NOTE: if adenopathy is noted on CT or whole-body PET/CT
scan, an endoscopic ultrasound is not required prior to STEP 2 registration as
long as adequate tissue has been obtained for central HER2 testing)

- Patients may have regional adenopathy including para-esophageal, gastric,
gastrohepatic and celiac nodes; if celiac adenopathy is present, it must be =< 2
cm

- Patients with tumors at the level of the carina or above must undergo
bronchoscopy to exclude fistula

- Zubrod performance status 0-2

- Absolute neutrophil count (ANC) >= 1,500 cells/mm^3

- Platelets >= 100,000 cells/mm^3

- Hemoglobin >= 8.0 g/dL (note: the use of transfusion or other intervention to achieve
hemoglobin [Hgb] >= 8.0 g/dL is acceptable)

- Creatinine =< 2 times upper limit of normal

- Bilirubin =< 1.5 times upper limit of normal

- Aspartate aminotransferase (AST) =< 3.0 times upper limit of normal

- For women of childbearing potential, a negative serum or urine pregnancy test

- Patients must sign a study-specific informed consent prior to study entry

- CONDITIONS FOR PATIENT ELIGIBILITY PRIOR TO STEP 2 REGISTRATION (HER2-POSITIVE
PATIENTS ONLY)

- HER2 expressing adenocarcinoma of the esophagus centrally

- Surgical consultation to confirm that patient will be able to undergo curative
resection after completion of chemoradiation within 56 days prior to step 2
registration

- Radiation oncology consultation to confirm that disease can be encompassed in a
radiotherapy field within 56 days prior to step 2 registration

- Consultation with a medical oncologist within 56 days prior to step 2 registration

- Stage T1N1-2, T2-3N0-2, according to the AJCC 7th edition staging, based upon the
following minimum diagnostic work-up:

- History/physical examination, with documentation of the patient's weight, within
14 days prior to step 2 registration

- Whole-body PET/CT scan within 56 days prior to step 2 registration (if only CT
performed prior to step 1 registration)

- Endoscopic ultrasound within 56 days prior to step 2 registration, unless the
patient is found to have adenopathy per CT or whole-body PET/CT scan

- Electrocardiogram (EKG) within 56 days prior to step 2 registration

- Serum creatinine =< 2 x the upper limit or normal within 14 days prior to step 2
registration

- Zubrod performance status 0-2 within 14 days prior to step 2 registration

- For women of childbearing potential, a negative serum pregnancy test within 14 days
prior to step 2 registration

- Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal by
cardiac echocardiogram (echo) or multi gated acquisition (MUGA) scan within 56 days
prior to step 2 registration

- Women of childbearing potential and sexually active male participants must agree to
practice adequate contraception while on study and for at least 60 days following the
last dose of chemotherapy or trastuzumab

Exclusion Criteria:

- Patients with cervical esophageal carcinoma

- Patients with T1N0 disease, T4 disease, and proximal esophageal cancers (15-24 cm)

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

- Prior radiation therapy for esophageal cancer or prior chest radiotherapy

- Prior anthracycline or taxane

- Evidence of tracheoesophageal fistula or invasion into the trachea or major bronchi

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

- Medical contraindications to esophagectomy

- Prior therapy with any agent targeting the HER2 pathway or human epidermal growth
factor receptor 1 (HER1) (epidermal growth factor receptor [EGFR]) pathway

- Prior therapy with trastuzumab

- Prior allergic reaction to the study drugs involved in this protocol or to a
monoclonal antibody

- Previous history of congestive heart failure

- Severe, active comorbidity, defined as follows:

- Unstable angina in the last 6 months

- Transmural myocardial infarction within the last 6 months

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

- 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; protocol-specific requirements may also exclude immunocompromised
patients

- Pregnant or nursing women or women of childbearing potential and men who are sexually
active and not willing/able to use medically acceptable forms of contraception