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A Phase III Trial Evaluating the Addition of Trastuzumab to Trimodality Treatment of HER2-Overexpressing Esophageal Adenocarcinoma

Phase 3
18 Years
Open (Enrolling)
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

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Trial Information

A Phase III Trial Evaluating the Addition of Trastuzumab to Trimodality Treatment of HER2-Overexpressing Esophageal Adenocarcinoma


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


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

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.


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 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 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.

Inclusion Criteria:

- Pathologically confirmed primary adenocarcinoma of the esophagus meeting the
following criteria:

- Involvement of mid (up to 25 cm), distal, or esophagogastric junction

- Involvement of the stomach up to 5 cm allowed

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

- Stage T1, N1-2 or T2-3, N0-2 disease by chest, abdominal, or pelvic CT scan or
whole-body PET/CT scan

- No T1,N0 or T4 disease

- No metastatic disease

- Regional adenopathy including para-esophageal, gastric, gastrohepatic, and
celiac (≤ 2 cm) nodes allowed

- No cervical esophageal or proximal esophageal (15-24 cm) carcinoma

- Intent to submit tissue for central HER2 testing

- Must have undergone endoscopy with biopsy

- HER2-overexpressing adenocarcinoma of the esophagus

- Disease must be encompassed in 1 radiotherapy field

- Able to undergo curative resection within 56 days after completion of chemoradiation

- No evidence of tracheoesophageal fistula or invasion into the trachea or major

- Zubrod performance status 0-2

- ANC ≥ 1,500 cells/mm³

- Platelet count ≥100,000 cells/mm³

- Hemoglobin (Hb) ≥ 8.0 g/dL (transfusion or other intervention to achieve Hb ≥ 8.0
g/dL allowed)

- Creatinine ≤ 2 times upper limit of normal (ULN)

- Bilirubin ≤ 1.5 times ULN

- AST ≤ 3.0 times ULN

- LVEF normal

- Negative pregnancy test

- Not pregnant or nursing

- Fertile patients must use effective contraception during and for ≥ 60 days after
completion of chemotherapy or trastuzumab

- No prior invasive malignancy except non-melanomatous skin cancer or curatively
treated carcinoma in situ of the breast, oral cavity, or cervix with no evidence of
disease within the past 2 years

- No medical contraindications to esophagectomy

- No prior allergic reaction to the study drugs involved in this protocol or to a
monoclonal antibody

- No history of congestive heart failure

- No severe or active comorbidity defined as any of the following:

- Unstable angina within the past 6 months

- Transmural myocardial infarction within the past 6 months

- Acute bacterial or fungal infection requiring intravenous antibiotics

- AIDS or immunocompromised patients

- HIV testing is not required

- No prior systemic chemotherapy for esophageal cancer

- Prior chemotherapy for a different cancer allowed

- No prior radiotherapy for esophageal cancer or prior chest radiotherapy

- No prior anthracycline or taxane

- No prior therapy with any agent targeting the HER2 pathway or HER1 (EGFR) pathway

- No prior trastuzumab

- No concurrent intensity-modulated radiotherapy

- No other concurrent radiotherapy

- No other concurrent investigational agents

- No other concurrent cytotoxic agents

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Disease-free survival (DFS)

Outcome Description:

DFS will be estimated by the Kaplan-Meier method. The distribution of DFS estimates between the 2 arms will be compared using the log rank test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with DFS.

Outcome Time Frame:

From the date of randomization to the date of first failure or last follow-up, assessed up to 8 years

Safety Issue:


Principal Investigator

Howard Safran

Investigator Role:

Principal Investigator

Investigator Affiliation:

Radiation Therapy Oncology Group


United States: Food and Drug Administration

Study ID:




Start Date:

July 2010

Completion Date:

Related Keywords:

  • 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
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Esophageal Diseases
  • Esophageal Neoplasms



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