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

Conditions

Adenocarcinoma of the Esophagus | Adenocarcinoma of the Gastroesophageal Junction | Stage IB Esophageal Cancer | Stage IIA Esophageal Cancer | Stage IIB Esophageal Cancer | Stage IIIA Esophageal Cancer | Stage IIIB Esophageal Cancer

Trial Phase

Phase 3

Trial Purpose and Description

Trial Purpose

This randomized phase III trial studies how well radiation therapy, paclitaxel, and carboplatin with or without trastuzumab work in treating patients with esophageal cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as paclitaxel and carboplatin, 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 trastuzumab, 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. It is not yet known whether giving radiation therapy and combination chemotherapy together with or without trastuzumab is more effective in treating esophageal cancer.


Trial Description


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.

TERTIARY 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: This is a multicenter study. Patients are stratified according to presence of
adenopathy (yes vs no), and involved celiac nodes (absent vs presence = 2 cm). 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 paclitaxel IV over 60 minutes and carboplatin IV over 30-60 minutes on days 1, 8,
15, 22, 29, and 36 and trastuzumab IV over 30-90 minutes on days 1, 8, 15, 22, 29, 36, and
57. 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.

Patients may undergo blood and tumor tissue samples collection (during surgery) for
correlative studies and tissue bank. Patients may complete the Functional Assessment of
Cancer Therapy for Esophageal Cancer (FACT-E) and the EuroQol (EQ-5D) questionnaires at
baseline and periodically during study.

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

Participation Guidelines

Age:
18 Years - N/A
Gender:
Both

Eligibility Criteria


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/mm³

- Platelets >=100,000 cells/mm³

- 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 (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
Sponsor:
National Cancer Institute (NCI)
Dates:
December 2010
Last Updated:
October 7, 2013
Study HIC#:

Clinicaltrials.gov ID: NCT01196390