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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01196390
Recruitment Status : Active, not recruiting
First Posted : September 8, 2010
Last Update Posted : May 13, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE September 4, 2010
First Posted Date  ICMJE September 8, 2010
Last Update Posted Date May 13, 2019
Actual Study Start Date  ICMJE December 30, 2010
Estimated Primary Completion Date April 30, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 5, 2013)
Disease-free survival (DFS) [ Time Frame: From the date of randomization to the date of first failure or last follow-up, assessed up to 8 years ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 4, 2010)
Disease-free survival
Change History Complete list of historical versions of study NCT01196390 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 25, 2019)
  • Pathologic complete response [ Time Frame: Within 4 weeks after surgical resection ]
    Pathologic complete response is defined as no viable residual tumor cells.
  • Overall survival (OS) [ Time Frame: From the date of randomization to the date of first failure or last follow-up, assessed up to 8 years ]
    OS will be estimated by the Kaplan-Meier method. The distribution of OS 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 OS.
  • Incidence of adverse events [ Time Frame: From the start of chemoradiation up to the earlier date of surgery or 6 weeks after completion of chemoradiation ]
    Will be assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (beginning April 1, 2018, CTCAE version 5.0 will be utilized).
  • Health-related quality of life (QOL) [ Time Frame: Up to 2 years ]
    Will be measured by Functional Assessment of Cancer Therapy-Esophageal (FACT-E). Distributions of QOL data collection patterns over all collection points in each treatment arm will be described. To inspect the missing data mechanism for each tool, at least a graphical method will be used.
  • Quality-adjusted survival [ Time Frame: Up to 2 years ]
    Will be assessed by the EuroQol 5-dimensional (EQ-5D). Quality-adjusted survival is calculated as the weighted sum of different time in different health states added up to a total quality-adjusted survival time [U=sum of quality (qi) of health states K times the duration (si) spent in each health state].
  • Molecular correlates of efficacy [ Time Frame: Up to 8 years ]
  • Predictors of cardiotoxicity [ Time Frame: Up to 8 years ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 4, 2010)
  • Pathologic complete response
  • Overall survival
  • Adverse events
  • Health-related quality of life as measured by FACT-E
  • Quality-adjusted survival
  • Molecular correlates of efficacy
  • Predictors of cardiotoxicity
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Radiation Therapy, Paclitaxel, and Carboplatin With or Without Trastuzumab in Treating Patients With Esophageal Cancer
Official Title  ICMJE A Phase III Trial Evaluating the Addition of Trastuzumab to Trimodality Treatment of HER2-Overexpressing Esophageal Adenocarcinoma
Brief Summary 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, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as trastuzumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving radiation therapy and combination chemotherapy together with or without trastuzumab is more effective in treating esophageal cancer.
Detailed 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.

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Esophageal Adenocarcinoma
  • Gastroesophageal Junction Adenocarcinoma
  • HER2/Neu Positive
  • Stage IB Esophageal Cancer AJCC v7
  • Stage IIA Esophageal Cancer AJCC v7
  • Stage IIB Esophageal Cancer AJCC v7
  • Stage IIIA Esophageal Cancer AJCC v7
  • Stage IIIB Esophageal Cancer AJCC v7
Intervention  ICMJE
  • Drug: Carboplatin
    Given IV
    Other Names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • Nealorin
    • Novoplatinum
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Paclitaxel
    Given IV
    Other Names:
    • Anzatax
    • Asotax
    • Bristaxol
    • Praxel
    • Taxol
    • Taxol Konzentrat
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Name: Quality of Life Assessment
  • Radiation: Radiation Therapy
    Undergo radiation therapy
    Other Names:
    • Cancer Radiotherapy
    • Irradiate
    • Irradiated
    • irradiation
    • Radiation
    • Radiotherapeutics
    • RADIOTHERAPY
    • RT
    • Therapy, Radiation
  • Procedure: Therapeutic Conventional Surgery
    Undergo surgery
  • Biological: Trastuzumab
    Given IV
    Other Names:
    • ABP 980
    • Anti-c-ERB-2
    • Anti-c-erbB2 Monoclonal Antibody
    • Anti-ERB-2
    • Anti-erbB-2
    • Anti-erbB2 Monoclonal Antibody
    • Anti-HER2/c-erbB2 Monoclonal Antibody
    • Anti-p185-HER2
    • c-erb-2 Monoclonal Antibody
    • HER2 Monoclonal Antibody
    • Herceptin
    • Herceptin Biosimilar PF-05280014
    • Herceptin Trastuzumab Biosimilar PF-05280014
    • MoAb HER2
    • Monoclonal Antibody c-erb-2
    • Monoclonal Antibody HER2
    • Ogivri
    • PF-05280014
    • rhuMAb HER2
    • RO0452317
    • Trastuzumab Biosimilar ABP 980
    • Trastuzumab Biosimilar HLX02
    • Trastuzumab Biosimilar PF-05280014
    • Trastuzumab-dkst
Study Arms  ICMJE
  • Experimental: Arm I (radiotherapy, chemotherapy, trastuzumab)
    Patients undergo radiotherapy once daily 5 days a week for 5.5 weeks. Patients also receive trastuzumab IV over 30-90 minutes on days 1, 8, 15, 22, 29, 36, and 57 and paclitaxel intravenously 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.
    Interventions:
    • Drug: Carboplatin
    • Other: Laboratory Biomarker Analysis
    • Drug: Paclitaxel
    • Other: Quality-of-Life Assessment
    • Radiation: Radiation Therapy
    • Procedure: Therapeutic Conventional Surgery
    • Biological: Trastuzumab
  • Experimental: Arm II (radiotherapy and chemotherapy)
    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.
    Interventions:
    • Drug: Carboplatin
    • Other: Laboratory Biomarker Analysis
    • Drug: Paclitaxel
    • Other: Quality-of-Life Assessment
    • Radiation: Radiation Therapy
    • Procedure: Therapeutic Conventional Surgery
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: January 15, 2015)
591
Original Estimated Enrollment  ICMJE
 (submitted: September 4, 2010)
480
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date April 30, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries India
 
Administrative Information
NCT Number  ICMJE NCT01196390
Other Study ID Numbers  ICMJE NCI-2011-02601
NCI-2011-02601 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000683717
RTOG-1010
RTOG-1010 ( Other Identifier: NRG Oncology )
RTOG-1010 ( Other Identifier: CTEP )
U10CA180830 ( U.S. NIH Grant/Contract )
U10CA180868 ( U.S. NIH Grant/Contract )
U10CA021661 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Howard P Safran NRG Oncology
PRS Account National Cancer Institute (NCI)
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP