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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01196390
First received: September 4, 2010
Last updated: June 23, 2014
Last verified: March 2014

September 4, 2010
June 23, 2014
December 2010
August 2018   (final data collection date for primary outcome measure)
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 ] [ Designated as safety issue: No ]
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.
Disease-free survival [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01196390 on ClinicalTrials.gov Archive Site
  • Pathologic complete response [ Time Frame: Within 4 weeks after surgical resection ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.
  • Adverse events [ Time Frame: From the start of chemoradiation up to the earlier date of surgery or 6 weeks after completion of chemoradiation ] [ Designated as safety issue: Yes ]
    Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
  • Health-related quality of life (QOL) as measured by FACT-E [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    The EQ-5D will be used to assess quality-adjusted survival. 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 ] [ Designated as safety issue: No ]
  • Predictors of cardiotoxicity [ Time Frame: Up to 8 years ] [ Designated as safety issue: Yes ]
  • Pathologic complete response [ Designated as safety issue: No ]
  • Overall survival [ Designated as safety issue: No ]
  • Adverse events [ Designated as safety issue: Yes ]
  • Health-related quality of life as measured by FACT-E [ Designated as safety issue: No ]
  • Quality-adjusted survival [ Designated as safety issue: No ]
  • Molecular correlates of efficacy [ Designated as safety issue: No ]
  • Predictors of cardiotoxicity [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Radiation Therapy, Paclitaxel, and Carboplatin With or Without Trastuzumab in Treating Patients With Esophageal Cancer
A Phase III Trial Evaluating The Addition Of Trastuzumab To Trimodality Treatment Of Her2-Overexpressing Esophageal Adenocarcinoma

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.

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • 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
  • Radiation: radiation therapy
    Undergo radiation therapy
    Other Names:
    • irradiation
    • radiotherapy
    • therapy, radiation
  • Drug: paclitaxel
    Given IV
    Other Names:
    • Anzatax
    • Asotax
    • TAX
    • Taxol
  • Drug: carboplatin
    Given IV
    Other Names:
    • Carboplat
    • CBDCA
    • JM-8
    • Paraplat
    • Paraplatin
  • Biological: trastuzumab
    Given IV
    Other Names:
    • anti-c-erB-2
    • Herceptin
    • MOAB HER2
  • Procedure: therapeutic conventional surgery
    Undergo surgery
  • Other: laboratory biomarker analysis
    Correlative studies
  • Procedure: quality-of-life assessment
    Ancillary studies
    Other Name: quality of life assessment
  • Experimental: Arm I (radiotherapy, chemotherapy, trastuzumab)
    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. Within 5-8 weeks after completion of radiotherapy, all patients undergo surgery. 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:
    • Radiation: radiation therapy
    • Drug: paclitaxel
    • Drug: carboplatin
    • Biological: trastuzumab
    • Procedure: therapeutic conventional surgery
    • Other: laboratory biomarker analysis
    • Procedure: quality-of-life assessment
  • 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:
    • Radiation: radiation therapy
    • Drug: paclitaxel
    • Drug: carboplatin
    • Procedure: therapeutic conventional surgery
    • Other: laboratory biomarker analysis
    • Procedure: quality-of-life assessment
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
480
Not Provided
August 2018   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
United States
 
NCT01196390
NCI-2011-02601, NCI-2011-02601, CDR0000683717, RTOG 1010, RTOG-1010, U10CA021661
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Howard Safran Radiation Therapy Oncology Group
National Cancer Institute (NCI)
March 2014

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