S0414 Cetuximab, Combo Chemo, and RT in Locally Advanced Esophageal Cancer

Cetuximab Plus Cisplatin, Irinotecan and Thoracic Radiotherapy (TRT) for Locally Advanced (Non-Metastatic), Clinically Unresectable Esophageal Cancer: A Phase II Trial With Molecular Correlates

RATIONALE: Monoclonal antibodies, such as cetuximab, 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. Cetuximab may also stop the growth of esophageal cancer by blocking blood flow to the tumor and by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cisplatin and irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving cetuximab together with combination chemotherapy and radiation therapy may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving cetuximab together with combination chemotherapy and radiation therapy works in treating patients with locally advanced esophageal cancer that cannot be removed by surgery.

Study Overview

• Status: Terminated
• Conditions: Esophageal Cancer
• Intervention / Treatment: Biological: cetuximab; Drug: cisplatin; Drug: irinotecan hydrochloride; Radiation: radiation therapy

Detailed Description

OBJECTIVES:

Primary

• Determine the 2-year overall survival of patients with previously untreated, clinically unresectable, locally advanced squamous cell carcinoma or adenocarcinoma of the esophagus treated with cetuximab, cisplatin, irinotecan, and thoracic radiotherapy.

Secondary

• Determine the toxicity profile of this regimen in these patients.
• Determine the probability of objective response (confirmed and unconfirmed, complete and partial) in patients with measurable disease treated with this regimen.
• Determine the time to progression in patients with measurable disease treated with this regimen.
• Correlate, preliminarily, gene expression (RNA) levels and germline polymorphisms of genes involved in DNA repair (e.g., ECRCC-1 and XRCC-1), drug metabolism (e.g., UGT1A1), and the epidermal growth factor receptor (EGFR) pathway (e.g., EGFR, interleukin-8, and vascular endothelial growth factor) with response, time to progression, overall survival, and toxicity in patients treated with this regimen. (This will not be completed as this study was closed due to poor accrual.)

OUTLINE: This is a multicenter study.

Patients receive cetuximab intravenous (IV) over 1-2 hours on days 1, 8, and 15. Patients also receive cisplatin IV and irinotecan IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Beginning on day 1 of course 3, patients undergo thoracic radiotherapy once daily 5 days a week for 5-6 weeks (total of 28 treatments).

After completion of study treatment, patients are followed at 4 weeks and then every 3-6 months for up to 5 years after study entry.

PROJECTED ACCRUAL: A total of 75-100 patients (75 with adenocarcinoma and 25 with squamous cell carcinoma) will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Mobile, Alabama, United States, 36652-2144
      • Mobile Infirmary Medical Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
  • California
    • Berkeley, California, United States, 94704
      • Alta Bates Comprehensive Cancer Center
    • Burbank, California, United States, 91505
      • Providence Saint Joseph Medical Center - Burbank
    • Burlingame, California, United States, 94010
      • Peninsula Medical Center
    • Castro Valley, California, United States, 94546
      • Eden Medical Center
    • Greenbrae, California, United States, 94904
      • Marin Cancer Institute at Marin General Hospital
    • Greenbrae, California, United States, 94904
      • Sutter Health - Western Division Cancer Research Group
    • Hayward, California, United States, 94545
      • Saint Rose Hospital
    • Los Angeles, California, United States, 90089-9181
      • USC/Norris Comprehensive Cancer Center and Hospital
    • Oakland, California, United States, 94609
      • Alta Bates Summit Medical Center - Summit Campus
    • Oakland, California, United States, 94602
      • Highland General Hospital
    • Oakland, California, United States, 94609
      • CCOP - Bay Area Tumor Institute
    • Palm Springs, California, United States, 92262
      • Desert Regional Medical Center Comprehensive Cancer Center
    • Pleasanton, California, United States, 94588
      • Valley Care Medical Center
    • Sacramento, California, United States, 95817
      • University of California Davis Cancer Center
    • San Francisco, California, United States, 94118
      • California Pacific Medical Center - California Campus
    • San Pablo, California, United States, 94806
      • Doctors Medical Center - San Pablo Campus
    • Sana Rosa, California, United States, 95405
      • CCOP - Santa Rosa Memorial Hospital
    • Vallejo, California, United States, 94589
      • Sutter Solano Medical Center
  • Colorado
    • Fort Collins, Colorado, United States, 80524
      • Poudre Valley Hospital
  • Florida
    • Lakeland, Florida, United States, 33804-5000
      • Watson Clinic, LLC
  • Georgia
    • Augusta, Georgia, United States, 30901
      • Augusta Oncology Associates - Walton Way
    • Savannah, Georgia, United States, 31403-3089
      • Curtis & Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center
    • Savannah, Georgia, United States, 31405
      • Nancy N. and J. C. Lewis Cancer and Research Pavilion at St. Joseph's/Candler
  • Idaho
    • Boise, Idaho, United States, 83712
      • St. Luke's Mountain States Tumor Institute - Boise
  • Illinois
    • Springfield, Illinois, United States, 62781-0001
      • Regional Cancer Center at Memorial Medical Center
  • Indiana
    • Beech Grove, Indiana, United States, 46107
      • St. Francis Hospital and Health Centers - Beech Grove Campus
    • Richmond, Indiana, United States, 47374
      • Reid Hospital & Health Care Services, Incorporated
  • Kansas
    • Chanute, Kansas, United States, 66720
      • Cancer Center of Kansas, PA - Chanute
    • Dodge City, Kansas, United States, 67801
      • Cancer Center of Kansas, PA - Dodge City
    • El Dorado, Kansas, United States, 67042
      • Cancer Center of Kansas, PA - El Dorado
    • Kansas City, Kansas, United States, 66160-7357
      • Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center
    • Kingman, Kansas, United States, 67068
      • Cancer Center of Kansas, PA - Kingman
    • Liberal, Kansas, United States, 67901
      • Southwest Medical Center
    • Newton, Kansas, United States, 67114
      • Cancer Center of Kansas, PA - Newton
    • Parsons, Kansas, United States, 67357
      • Cancer Center of Kansas, PA - Parsons
    • Pratt, Kansas, United States, 67124
      • Cancer Center of Kansas, PA - Pratt
    • Salina, Kansas, United States, 67042
      • Cancer Center of Kansas, PA - Salina
    • Salina, Kansas, United States, 67401
      • Tammy Walker Cancer Center at Salina Regional Health Center
    • Wellington, Kansas, United States, 67152
      • Cancer Center of Kansas, PA - Wellington
    • Wichita, Kansas, United States, 67214
      • Wesley Medical Center
    • Wichita, Kansas, United States, 67203
      • Associates in Womens Health, PA - North Review
    • Wichita, Kansas, United States, 67208
      • Cancer Center of Kansas, PA - Medical Arts Tower
    • Wichita, Kansas, United States, 67214
      • Cancer Center of Kansas, PA - Wichita
    • Wichita, Kansas, United States, 67214
      • CCOP - Wichita
    • Wichita, Kansas, United States, 67214
      • Via Christi Cancer Center at Via Christi Regional Medical Center
    • Winfield, Kansas, United States, 67156
      • Cancer Center of Kansas, PA - Winfield
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0293
      • Markey Cancer Center at University of Kentucky Chandler Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0942
      • University of Michigan Comprehensive Cancer Center
    • Battle Creek, Michigan, United States, 49017
      • Battle Creek Health System Cancer Care Center
    • Big Rapids, Michigan, United States, 49307
      • Mecosta County Medical Center
    • Detroit, Michigan, United States, 48202
      • Josephine Ford Cancer Center at Henry Ford Hospital
    • Grand Rapids, Michigan, United States, 49503
      • CCOP - Grand Rapids
    • Grand Rapids, Michigan, United States, 49503
      • Lacks Cancer Center at Saint Mary's Health Care
    • Grand Rapids, Michigan, United States, 49506
      • Metro Health Hospital
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health Hospital - Butterworth Campus
    • Holland, Michigan, United States, 49423
      • Holland Community Hospital
    • Muskegon, Michigan, United States, 49442
      • Hackley Hospital
    • Traverse City, Michigan, United States, 49684
      • Munson Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64131
      • CCOP - Kansas City
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis University Cancer Center
    • Springfield, Missouri, United States, 65802
      • CCOP - Cancer Research for the Ozarks
    • Springfield, Missouri, United States, 65804
      • St. John's Regional Health Center
    • Springfield, Missouri, United States, 65807
      • Hulston Cancer Center at Cox Medical Center South
  • Montana
    • Billings, Montana, United States, 59101
      • CCOP - Montana Cancer Consortium
    • Billings, Montana, United States, 59101
      • Hematology-Oncology Centers of the Northern Rockies - Billings
    • Billings, Montana, United States, 59101
      • Northern Rockies Radiation Oncology Center
    • Billings, Montana, United States, 59101
      • St. Vincent Healthcare Cancer Care Services
    • Billings, Montana, United States, 59107-7000
      • Billings Clinic - Downtown
    • Bozeman, Montana, United States, 59715
      • Bozeman Deaconess Cancer Center
    • Butte, Montana, United States, 59701
      • St. James Healthcare Cancer Care
    • Great Falls, Montana, United States, 59405
      • Great Falls Clinic - Main Facility
    • Great Falls, Montana, United States, 59405
    • Helena, Montana, United States, 59601
      • St. Peter's Hospital
    • Kalispell, Montana, United States, 59901
      • Kalispell Regional Medical Center
    • Kalispell, Montana, United States, 59901
      • Glacier Oncology, PLLC
    • Kalispell, Montana, United States, 59901
      • Kalispell Medical Oncology at KRMC
    • Missoula, Montana, United States, 59801
      • Community Medical Center
    • Missoula, Montana, United States, 59804
      • Guardian Oncology and Center for Wellness
    • Missoula, Montana, United States, 59807-7877
      • Montana Cancer Specialists at Montana Cancer Center
    • Missoula, Montana, United States, 59807
      • Montana Cancer Center at St. Patrick Hospital and Health Sciences Center
  • Nebraska
    • Kearney, Nebraska, United States, 68848-1990
      • Good Samaritan Cancer Center at Good Samaritan Hospital
  • New York
    • Rochester, New York, United States, 14642
      • James P. Wilmot Cancer Center at University of Rochester Medical Center
    • Rochester, New York, United States, 14623
      • Interlakes Oncology/Hematology PC
  • North Carolina
    • Goldsboro, North Carolina, United States, 27534
      • Wayne Memorial Hospital, Incorporated
  • Ohio
    • Akron, Ohio, United States, 44307
      • McDowell Cancer Center at Akron General Medical Center
    • Dayton, Ohio, United States, 45428
      • Veterans Affairs Medical Center - Dayton
    • Dayton, Ohio, United States, 45405
      • Grandview Hospital
    • Dayton, Ohio, United States, 45406
      • Good Samaritan Hospital
    • Dayton, Ohio, United States, 45409
      • David L. Rike Cancer Center at Miami Valley Hospital
    • Dayton, Ohio, United States, 45415
      • Samaritan North Cancer Care Center
    • Dayton, Ohio, United States, 45429
      • CCOP - Dayton
    • Findlay, Ohio, United States, 45840
      • Blanchard Valley Medical Associates
    • Kettering, Ohio, United States, 45429
      • Charles F. Kettering Memorial Hospital
    • Middletown, Ohio, United States, 45044
      • Middletown Regional Hospital
    • Troy, Ohio, United States, 45373-1300
      • UVMC Cancer Care Center at Upper Valley Medical Center
    • Xenia, Ohio, United States, 45385
      • Ruth G. McMillan Cancer Center at Greene Memorial Hospital
  • Oregon
    • Gresham, Oregon, United States, 97030
      • Legacy Mount Hood Medical Center
    • Milwaukie, Oregon, United States, 97222
      • Providence Milwaukie Hospital
    • Portland, Oregon, United States, 97227
      • Northwest Cancer Specialists at Rose Quarter Cancer Center
    • Portland, Oregon, United States, 97213-2967
      • Providence Cancer Center at Providence Portland Medical Center
    • Portland, Oregon, United States, 97225
      • CCOP - Columbia River Oncology Program
    • Portland, Oregon, United States, 97225
      • Providence St. Vincent Medical Center
    • Portland, Oregon, United States, 97210
      • Legacy Good Samaritan Hospital & Medical Center Comprehensive Cancer Center
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Hospital and Health Center & Children's Hospital
    • Portland, Oregon, United States, 97239-3098
      • Oregon Health & Science University Cancer Institute
    • Salem, Oregon, United States, 97309-5014
      • Salem Hospital Regional Cancer Care Services
    • Tualatin, Oregon, United States, 97062
      • Legacy Meridian Park Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Hollings Cancer Center at Medical University of South Carolina
    • Charleston, South Carolina, United States, 29401
      • Roper St. Francis Cancer Center at Roper Hospital
    • Greenville, South Carolina, United States, 29615
      • CCOP - Greenville
  • Tennessee
    • Kingsport, Tennessee, United States, 37662
      • Christine LaGuardia Phillips Cancer Center at Wellmont Holston Valley Medical Center
    • Knoxville, Tennessee, United States, 37920-6999
      • U.T. Cancer Institute at University of Tennessee Medical Center
  • Virginia
    • Danville, Virginia, United States, 24541
      • Danville Regional Medical Center
    • Norton, Virginia, United States, 24273
      • Southwest Virginia Regional Cancer Center
  • Washington
    • Bellingham, Washington, United States, 98225
      • St. Joseph Cancer Center
    • Bremerton, Washington, United States, 98310
      • Olympic Hematology and Oncology
    • Kennewick, Washington, United States, 99336
      • Columbia Basin Hematology
    • Mt. Vernon, Washington, United States, 98273
      • Skagit Valley Hospital Cancer Care Center
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center
    • Seattle, Washington, United States, 98104
      • Fred Hutchinson Cancer Research Center
    • Seattle, Washington, United States, 98104
      • Minor and James Medical, PLLC
    • Seattle, Washington, United States, 98112
      • Group Health Central Hospital
    • Seattle, Washington, United States, 98122-4307
      • Swedish Cancer Institute at Swedish Medical Center - First Hill Campus
    • Seattle, Washington, United States, 98122
      • Polyclinic First Hill
    • Seattle, Washington, United States, 98195-6043
      • University Cancer Center at University of Washington Medical Center
    • Spokane, Washington, United States, 99202
      • Cancer Care Northwest - Spokane South
    • Vancouver, Washington, United States, 98684
      • Northwest Cancer Specialists at Vancouver Cancer Center
    • Vancouver, Washington, United States, 98668
      • Southwest Washington Medical Center Cancer Center
    • Wenatchee, Washington, United States, 98801-2028
      • Wenatchee Valley Medical Center
  • Wyoming
    • Sheridan, Wyoming, United States, 82801
      • Welch Cancer Center at Sheridan Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed primary squamous cell carcinoma or adenocarcinoma of the thoracic esophagus (≥ 20 cm from the incisors*) or the gastroesophageal junction (confined to ≤ 2 cm into the gastric cardia)

  • Disease confined to the esophagus or peri-esophageal soft tissue
  • T4, M0 disease
  • Surgically unresectable disease by esophageal endoscopic ultrasonography OR medically unresectable disease

NOTE: *Patients with primary disease < 26 cm from the incisors must undergo bronchoscopy AND have negative cytology within the past 4 weeks

• Measurable or non-measurable disease by x-ray, CT scan and/or MRI, or physical examination within the past 4 weeks (for measurable disease) or within the past 6 weeks (for non-measurable disease)
• Tumor specimens available
• No recurrent disease

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Zubrod 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count (ANC) ≥ 1,500/mm^3
• White Blood Cell (WBC) count ≥ 3,000/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 10.0 g/dL

Hepatic

• Albumin normal
• Bilirubin normal
• Alkaline phosphatase normal
• Serum glutamic oxaloacetic transaminase (SGOT) or Serum glutamic pyruvic transaminase (SGPT) ≤ 2.5 times upper limit of normal

Renal

• Creatinine clearance > 50 mL/min

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception
• No prior severe reaction to monoclonal antibodies
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy for esophageal cancer

Endocrine therapy

• Not specified

Radiotherapy

• No prior radiotherapy for esophageal cancer
• No concurrent intensity modulated radiotherapy
• No concurrent cobalt-60

Surgery

• No prior surgical resection or attempted surgical resection of esophageal cancer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment; Cetuximab+Cisplatin+Irinotecan followed by radiation therapy (RT) in Cycle 3.

Biological: cetuximab; 400mg/m^2 loading dose, intravenous (IV) over 120 min, day 1 of cycle 1 only. 250mg/m^2 maintenance dose, IV over 60 min, Days 8 & 15 of Cycle 1 and Days 1, 8, and 15 of subsequent cycles.; Other Names: Erbitux; Drug: cisplatin; 30mg/m^2, bolus intravenous (IV), on Days 1 & 8 of each cycle.; Other Names: Platinol; Drug: irinotecan hydrochloride; 65mg/m^2, intravenous (IV) over 30 min, on Days 1 & 8 of each cycle.; Other Names: CPT-11; Radiation: radiation therapy; The total dose to the prescription point will be 5,040 cGy given in 28 fractions. The patient will be treated with one fraction per day with all fields treated per day. 180 cGy will be delivered to the isocenter. The dose variation in the planning target volume (PTV) will be +7% and -5% of the prescription point dose.; Other Names: RT; TRT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival at 2 Years	Measured from time of registration to date of death due to any cause, or last contact date	0-2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug	Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal.	Patients were assessed for adverse events after every two cycles of chemotherapy.
Objective Response (Confirmed and Unconfined, Complete and Partial)	Complete response (CR) is complete disappearance of all measurable and non-measurable disease. No new lesions. No disease related symptoms. Normalization of markers and other abnormal lab values. Partial response (PR) applies only to patients with at least one measurable lesion. Greater than or equal to 30% decrease under baseline of the sum of longest diameters of all target measurable lesions. No unequivocal progression of non-measurable disease. No new lesions. Confirmation of CR or PR means a repeat scan at least 4 weeks apart documented before progression or symptomatic deterioration.	at week 16, then every 3 months until progression
Progression Free Survival	Measured from date of registration to date of first observation of progression or symptomatic deterioration. Patients last known to be alive and progression-free are censored at date of last contact.	0 - 5 years

Collaborators and Investigators

• Sponsor: Southwest Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Lisa Hammond, MD, The University of Texas Health Science Center at San Antonio; Study Chair: Charles R. Thomas, MD, OHSU Knight Cancer Institute; Study Chair: Charles D. Blanke, MD, FACP, OHSU Knight Cancer Institute; Study Chair: Vivek Mehta, MD, Swedish Cancer Institute at Swedish Medical Center - First Hill Campus

Study record dates

Study Major Dates

• Study Start: May 1, 2005
• Primary Completion (Actual): September 1, 2009
• Study Completion (Actual): May 1, 2012

Study Registration Dates

• First Submitted: May 3, 2005
• First Submitted That Met QC Criteria: May 3, 2005
• First Posted (Estimate): May 4, 2005

Study Record Updates

• Last Update Posted (Estimate): November 18, 2015
• Last Update Submitted That Met QC Criteria: November 16, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: stage III esophageal cancer; squamous cell carcinoma of the esophagus; adenocarcinoma of the esophagus
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Esophageal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Topoisomerase I Inhibitors; Cisplatin; Irinotecan; Cetuximab
• Other Study ID Numbers: CDR0000426442; U10CA032102 (U.S. NIH Grant/Contract); S0414 (Other Identifier: SWOG)