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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



Memorial Sloan Kettering Cancer Center New York, New York  10021
Mayo Clinic Rochester, Minnesota  55905
University of Iowa Hospitals and Clinics Iowa City, Iowa  52242
University of Mississippi Medical Center Jackson, Mississippi  39216-4505
Washington University School of Medicine Saint Louis, Missouri  63110
Fox Chase Cancer Center Philadelphia, Pennsylvania  19111
Medical University of South Carolina Charleston, South Carolina  29425-0721
University of Washington Medical Center Seattle, Washington  98195-6043
Rhode Island Hospital Providence, Rhode Island  02903
Porter Adventist Hospital Denver, Colorado  80210
Swedish Medical Center Englewood, Colorado  80110
North Suburban Medical Center Thornton, Colorado  80229
West Michigan Cancer Center Kalamazoo, Michigan  49007-3731
Geisinger Medical Center Danville, Pennsylvania  17822-0001
Loyola University Medical Center Maywood, Illinois  60153
Massachusetts General Hospital Cancer Center Boston, Massachusetts  02114
Northwest Community Hospital Arlington Heights, Illinois  60005
Beth Israel Medical Center New York, New York  10003
Akron General Medical Center Akron, Ohio  44302
Reading Hospital and Medical Center Reading, Pennsylvania  19612-6052
University of Texas Medical Branch Galveston, Texas  77555-1329
Dana-Farber Cancer Institute Boston, Massachusetts  02115
University of Kansas Medical Center Kansas City, Kansas  66160-7353
Kaiser Permanente Medical Center - Santa Clara Santa Clara, California  95051-5386
Carolinas Medical Center Charlotte, North Carolina  28232-2861
University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma  73104
Iowa Methodist Medical Center Des Moines, Iowa  50309
Medical Center of Central Georgia Macon, Georgia  31201
MetroHealth Medical Center Cleveland, Ohio  44109
Central Baptist Hospital Lexington, Kentucky  40503
Trinity Cancer Care Center Minot, North Dakota  58701
Advocate Christ Medical Center Oak Lawn, Illinois  60453
Montefiore Medical Center Bronx, New York  10467-2490
North Colorado Medical Center Greeley, Colorado  80631
McKee Medical Center Loveland, Colorado  80539
Rocky Mountain Cancer Center Denver, Colorado  80218
University of New Mexico Cancer Center Albuquerque, New Mexico  87131-5636
Methodist Estabrook Cancer Center Omaha, Nebraska  68114-4199
Cancer Centers of the Carolinas Greenville, South Carolina  29605
Paoli Memorial Hospital Paoli, Pennsylvania  19301-1792
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center Columbus, Ohio  43210-1240
Sutter Solano Medical Center Vallejo, California  94589
Piedmont Hospital Atlanta, Georgia  30309
Bryn Mawr Hospital Bryn Mawr, Pennsylvania  19010
Danville Regional Medical Center Danville, Virginia  24541
Exempla Lutheran Medical Center Wheat Ridge, Colorado  80033
Mayo Clinic Hospital Phoenix, Arizona  85054-4502
Poudre Valley Radiation Oncology Fort Collins, Colorado  80528
Bixby Medical Center Adrian, Michigan  49221
Saint Joseph Mercy Hospital Ann Arbor, Michigan  48106
Abbott-Northwestern Hospital Minneapolis, Minnesota  55407
Regions Hospital Saint Paul, Minnesota  55101
Northeast Georgia Medical Center Gainesville, Georgia  30501
Miami Valley Hospital Dayton, Ohio  45409
Cancer Treatment Center Wooster, Ohio  44691
Saint Joseph's Hospital Marshfield, Wisconsin  54449
Diagnostic and Treatment Center Weston, Wisconsin  54476
Singing River Hospital Pascagoula, Mississippi  39581
Methodist Hospital Houston, Texas  77030
Martin Memorial Cancer Center Stuart, Florida  34995-9010
Greater Baltimore Medical Center Baltimore, Maryland  21204
Cancer Centers of the Carolinas - Seneca Seneca, South Carolina  29672
Cancer Centers of the Carolinas - Spartanburg Spartanburg, South Carolina  29307
Mayo Clinic in Arizona Scottsdale, Arizona  85259-5404
Memorial Medical Center Springfield, Illinois  62781
University of Alabama at Birmingham Birmingham, Alabama  35294-3300
Providence Hospital Mobile, Alabama  36608
Vanderbilt University Nashville, Tennessee  37232-6305
Northwestern University Chicago, Illinois  60611
Northwest Cancer Specialists Vancouver, Washington  98664
Cancer Care Center, Incorporated Salem, Ohio  44460
University of Rochester Rochester, New York  14642
Glens Falls Hospital Glens Falls, New York  12801
Case Western Reserve University Cleveland, Ohio  44106
Yale University New Haven, Connecticut  06520
Emory University Atlanta, Georgia  30322
University of Pittsburgh Medical Center - Shadyside Hospital Pittsburgh, Pennsylvania  15213-2582
Providence Portland Medical Center Portland, Oregon  97213-3635
University of Texas Southwestern Medical Center Dallas, Texas  
University of Kentucky Lexington, Kentucky  40536-0098
Flower Hospital Sylvania, Ohio  43560-2197
UC Davis Comprehensive Cancer Center Sacramento, California  95817
Decatur Memorial Hospital Decatur, Illinois  62526
Lankenau Hospital Wynnewood, Pennsylvania  19096
Memorial Health University Medical Center Savannah, Georgia  31404
University of Southern California Los Angeles, California  90033
Rohnert Park Cancer Center Rohnert Park, California  94928
South Sacramento Cancer Center Sacramento, California  95823
University of Cincinnati Cincinnati, Ohio  45267-0502
Piedmont Fayette Hospital Fayetteville, Georgia  30214
Clackamas Radiation Oncology Center Clackamas, Oregon  97015
Froedtert and the Medical College of Wisconsin Milwaukee, Wisconsin  53226
Penrose-Saint Francis Healthcare Colorado Springs, Colorado  80907
Saint Francis Hospital and Medical Center Hartford, Connecticut  06105
Saint Joseph's-Candler Health System Savannah, Georgia  31405
Saint Francis Hospital and Health Centers Beech Grove, Indiana  46107
McFarland Clinic Ames, Iowa  50010
Mercy Hospital Cedar Rapids, Iowa  52403
Ochsner Clinic CCOP New Orleans, Louisiana  70121
Saint John Hospital and Medical Center Detroit, Michigan  48236
Saint John Macomb-Oakland Hospital Warren, Michigan  48093
Minnesota Oncology Hematology PA-Maplewood Maplewood, Minnesota  55109
North Memorial Medical Health Center Robbinsdale, Minnesota  55422
Saint Louis-Cape Girardeau CCOP Saint Louis, Missouri  63141
Saint John's Mercy Medical Center Saint Louis, Missouri  63141
Saint John's Hospital Springfield, Missouri  65804
Cox Medical Center Springfield, Missouri  65807
Billings Clinic Billings, Montana  59107-7000
Cooper Hospital University Medical Center Camden, New Jersey  08103
Fox Chase Cancer Center at Virtua Memorial Hospital of Burlington County Mount Holly, New Jersey  08060
Sparta Cancer Treatment Center Sparta, New Jersey  07871
Saint Luke's Roosevelt Hospital Center - Saint Luke's Division New York, New York  10025
Columbia University Medical Center New York, New York  10032
Highland Hospital Rochester, New York  14620
Kinston Medical Specialists PA Kinston, North Carolina  28501
Summa Barberton Hospital Barberton, Ohio  44203
Kettering Medical Center Kettering, Ohio  45429
Saint Charles Hospital Oregon, Ohio  43616
North Coast Cancer Care Sandusky, Ohio  44870
Mercy Cancer Center at Saint Anne Mercy Hospital Toledo, Ohio  43623
Providence Saint Vincent Medical Center Portland, Oregon  97225
Salem Hospital Salem, Oregon  97309
Aria Health-Torresdale Campus Philadelphia, Pennsylvania  19114
Geisinger Wyoming Valley Wilkes-Barre, Pennsylvania  18711
Greenville CCOP Greenville, South Carolina  29615
Swedish Medical Center-First Hill Seattle, Washington  98122-4307
Northwest CCOP Tacoma, Washington  98405
Wheeling Hospital Wheeling, West Virginia  26003
Sacred Heart Hospital Eau Claire, Wisconsin  54701
Saint Vincent Hospital Green Bay, Wisconsin  54301
Saint Mary's Hospital Green Bay, Wisconsin  54303
Bay Area Medical Center Marinette, Wisconsin  54143
Marshfield Clinic-Minocqua Center Minocqua, Wisconsin  54548
Marshfield Clinic-Rice Lake Center Rice Lake, Wisconsin  54868
Saint Michael's Hospital Stevens Point, Wisconsin  54481
University of California Medical Center At Irvine-Orange Campus Orange, California  92868
University of Maryland Greenebaum Cancer Center Baltimore, Maryland  21201
Northeast Radiation Oncology Center Dunmore, Pennsylvania  18512
Lake University Ireland Cancer Center Mentor, Ohio  44060
University of Illinois Chicago, Illinois  60612
Lahey Clinic Medical Center Burlington, Massachusetts  01805
Maine Medical Center- Scarborough Campus Scarborough, Maine  04074
University of Michigan University Hospital Ann Arbor, Michigan  48109
Renown Regional Medical Center Reno, Nevada  89502
UMDNJ - New Jersey Medical School Newark, New Jersey  07103
Carolinas Medical Center - Northeast Concord, North Carolina  28025
Rex Cancer Center Raleigh, North Carolina  27607
Cancer Centers of the Carolinas - Faris Greenville, South Carolina  29605
Cancer Centers of the Carolinas-Greer Radiation Oncology Greer, South Carolina  29650
Intermountain Medical Center Murray, Utah  84157
Dixie Medical Center Regional Cancer Center Saint George, Utah  84770
Utah Cancer Specialists-Salt Lake City Salt Lake City, Utah  84106
West Virginia University Charleston Charleston, West Virginia  25304
Grady Health System Atlanta, Georgia  30303
Kaiser Permanente Oakland-Broadway Oakland, California  94611
Kaiser Permanente-Rancho Cordova Cancer Center Rancho Cardova, California  95670
The Permanente Medical Group-Roseville Radiation Oncology Roseville, California  95678
Kaiser Permanente Radiation Oncology Cancer Treatment Center Santa Clara, California  95051
Kaiser Permanente Cancer Treatment Center South San Francisco, California  94080
Kansas City CCOP Prairie Village, Kansas  66208
Wentworth-Douglass Hospital Dover, New Hampshire  03820
UHHS-Chagrin Highlands Medical Center Orange Village, Ohio  44122
Southern Ohio Medical Center Portsmouth, Ohio  45662
UHHS-Westlake Medical Center Westlake, Ohio  44145
Gundersen Lutheran La Crosse, Wisconsin  54601
Robinson Radiation Oncology Ravenna, Ohio  44266
Los Angeles County-USC Medical Center Los Angeles, California  90033
Stanford University Hospitals and Clinics Stanford, California  94305
Siouxland Hematology Oncology Associates Sioux City, Iowa  51101
American College of Radiology Imaging Network Philadelphia, Pennsylvania  19103
The Kirklin Clinic at Acton Road Birmingham, Alabama  35243
Radiation Oncology Associates PC Fort Wayne, Indiana  46804
Enloe Medical Center Chico, California  95926
Summa Akron City Hospital Akron, Ohio  44304
William Backus Hospital Norwich, Connecticut  06360
D'Amour Center for Cancer Care Springfield, Massachusetts  01107
Barnes West County Hospital Saint Louis, Missouri  63141
Siteman Cancer Center - Saint Peters Saint Peters, Missouri  63376
The Cooper Cancer Institute-Voorhees Voorhees, New Jersey  08043
Radiation Oncology Associates Incorporated Providence, Rhode Island  02904
Zablocki Veterans Administration Medical Center Milwaukee, Wisconsin  53295
Door County Cancer Center Sturgeon Bay, Wisconsin  54235-1495
Franciscan St. Francis Health Indianapolis, Indiana  46237
PeaceHealth Saint Joseph Medical Center Bellingham, Washington  98225
Christiana Care Health System-Christiana Hospital Newark, Delaware  19718
Memorial Sloan-Kettering Cancer Center at Suffolk Commack, New York  11725
PeaceHealth Southwest Medical Center Vancouver, Washington  98664
IU Health Ball Memorial Hospital Muncie, Indiana  47303
Cape Radiation Oncology Cape Girardeau, Missouri  63703
Memorial Sloan Kettering Cancer Center at Basking Ridge Basking Ridge, New Jersey  07920
Memorial Sloan-Kettering Cancer Center Rockville Centre Rockville Centre, New York  11570
Memorial Sloan-Kettering Cancer Center at Phelps Sleepy Hollow, New York  10591
Rocky Mountain Cancer Center North Thornton, Colorado  80221
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