Panitumumab, Docetaxel, Cisplatin, Radiation Therapy, and Surgery in Treating Patients With Newly Diagnosed, Locally Advanced Esophageal Cancer or Cancer of the Gastroesophageal Junction

A Phase II Study of Neoadjuvant Therapy With Cisplatin, Docetaxel, Panitumumab Plus Radiation Therapy Followed by Surgery in Patients With Locally Advanced Adenocarcinoma of the Distal Esophagus

RATIONALE: Monoclonal antibodies, such as panitumumab, 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. Drugs used in chemotherapy, such as cisplatin and docetaxel, work in different ways to kill tumor cells or stop them from growing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving combination chemotherapy together with panitumumab and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

PURPOSE: This phase II trial is studying how well giving panitumumab together with docetaxel, cisplatin, radiation therapy, and surgery works in treating patients with newly diagnosed, locally advanced esophageal cancer or cancer of the gastroesophageal junction.

Study Overview

• Status: Completed
• Conditions: Esophageal Cancer; Adenocarcinoma of the Gastroesophageal Junction
• Intervention / Treatment: Drug: docetaxel; Radiation: radiation therapy; Procedure: therapeutic conventional surgery; Procedure: neoadjuvant therapy; Drug: cisplatin; Biological: panitumumab

Detailed Description

OBJECTIVES:

Primary

• To determine the pathologic complete response rate in patients with newly diagnosed, locally advanced adenocarcinoma of the distal esophagus or gastroesophageal junction treated with neoadjuvant panitumumab and combination chemoradiotherapy followed by surgery.

Secondary

• To determine the near-complete pathologic response rate in the primary tumor (≤ 10% residual viable cancer).
• To determine the overall survival and disease-free survival rates of these patients.
• To determine the safety profile of this regimen.

OUTLINE: Patients receive panitumumab IV over 1 hour, docetaxel IV over 1 hour, and cisplatin IV over 1-2 hours on day 1 in weeks 1, 3, 5, 7, and 9. Patients also undergo radiotherapy once daily 5 days a week beginning in week 5 and continuing for 5.5 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Beginning 6-9 weeks after completion of chemoradiotherapy, patients with no evidence of metastatic disease undergo esophagectomy.

After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 1 year OR every 6 months for 3 years.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Savannah, Georgia, United States, 31403-3089
      • Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
    • Chicago, Illinois, United States, 60611-3013
      • Robert H. Lurie Comprehensive Cancer Center at Northwestern University
    • Evanston, Illinois, United States, 60201-1781
      • Evanston Hospital
    • Springfield, Illinois, United States, 62794-9677
      • Simmons Cooper Cancer Institute
  • Kentucky
    • Lexington, Kentucky, United States, 40503-9985
      • Central Baptist Hospital
  • Michigan
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital - Royal Oak Campus
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756-0002
      • Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28232-2861
      • Blumenthal Cancer Center at Carolinas Medical Center
    • Winston-Salem, North Carolina, United States, 27157-1096
      • Wake Forest University Comprehensive Cancer Center
  • Ohio
    • Dayton, Ohio, United States, 45406
      • Good Samaritan Hospital
    • Greenville, Ohio, United States, 45331
      • Wayne Hospital
    • Kettering, Ohio, United States, 45429
      • Charles F. Kettering Memorial Hospital
  • Oregon
    • Portland, Oregon, United States, 97213-2967
      • Providence Cancer Center at Providence Portland Medical Center
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Hospital and Health Center and Children's Hospital
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822-0001
      • Geisinger Cancer Institute at Geisinger Health
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Cancer Centers
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny Cancer Center at Allegheny General Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Hollings Cancer Center at Medical University of South Carolina

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

1. ≥ 18 years old
2. ECOG/Zubrod Performance Status 0-1

3. Biopsy-proven resectable primary (nonrecurrent) adenocarcinoma of the distal esophagus or GE junction (Siewert Type I or II)

   • Siewert Type I: adenocarcinoma of the distal esophagus
   • Siewert Type II: adenocarcinoma of the esophago-gastric junction/real cardia
4. Pre-registration EUS, CT of chest and upper abdomen, and PET must support a clinical stage of T3N0M0, T2-3N1M0 or T2-3N0-1M1a (celiac adenopathy must be ≤ 2 cm by EUS). Clinically staged T1 tumors and T2N0M0 tumors are not eligible. N1 does not require biopsy/FNA. Note: Patients requiring a stent for nutrition must have staging examinations and scans completed before stent placement.
5. No definitive radiological evidence of distant metastases.
6. No pre-existing grade 2 or greater peripheral neuropathy (CTCAE v3) of any etiology.

7. Adequate bone marrow, hepatic and renal function prior to registration:

   • WBC ≥ 3,000/mm³
   • ANC ≥ 1,500/mm³
   • Platelet count ≥ 100,000/mm³
   • Hemoglobin ≥ 9.5 g/dL
   • Creatinine ≤ 1.5 mg/dL
   • Total bilirubin ≤ 3 mg/dL
   • AST (SGOT) ≤ 2.0 times upper limit of normal (ULN)
   • ALT (SGPT) ≤ 2.0 times ULN
   • Alkaline phosphatase ≤ 2.0 times ULN
   • Albumin ≥ 2.0 g/dL OR prealbumin ≥ 15 mg/dL
   • Magnesium ≥ lower limit of normal (LLN)
8. Patient must be evaluated before registration by medical oncologist, radiation oncologist and surgeon and deemed fit for protocol therapy and surgery.
9. No prior invasive malignancy, unless disease-free for ≥ 5 years prior to registration (Exceptions: non-melanoma skin cancer, in-situ cancers).
10. Non-pregnant and non-breast feeding. Female participants of child-bearing potential must have a negative urine or serum pregnancy test prior to registration. Perimenopausal participants must be amenorrheic ≥ 12 months to be considered not of childbearing potential. All patients of reproductive potential must agree to use an an effective method of birth-control while receiving study therapy and for six months after completion of therapy.
11. No prior chest or upper abdomen radiotherapy; prior therapy with cisplatin, docetaxel, panitumumab or other anti-EGFR therapy or prior esophageal or gastric surgery (Exception: prior surgery to treat reflux disease)
12. No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psyschiatric illness/social situations that would limit compliance with study requirements.
13. No history of interstitial lung disease (eg, pneumonitis or pulmonary fibrosis or any evidence of interstitial lung disease on baseline chest CT scan
14. No history of any medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risks associated with the study participation or investigational product(s) administration or may interfere with the interpretation of the results.

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
Other: Docetaxel + Cisplatin + Panitumumab + RT; Patients received docetaxel (40 mg/m^2), cisplatin (40 mg/m^2) and panitumumab (6 mg/kg) on weeks 1, 3, 5, 7, and 9 with radiotherapy (RT) (5040 cGy, 180 cGy/day x 28 days) beginning week 5. Resection was planned after completing chemotherapy (CRT).	Drug: docetaxel; Radiation: radiation therapy; Procedure: therapeutic conventional surgery; Procedure: neoadjuvant therapy; Drug: cisplatin; Biological: panitumumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Pathologic Complete Response Following Surgery	Pathologic complete response (pCR) was defined as no viable residual tumor cells. A cellular residual mucin pools should be noted but also considered a pathologic complete response.	Post surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Near-complete Response Rate (≤ 10% Residual Cancer in Primary Tumor Viable)		Post surgery
Percentage of Participants With 3-year Overall Survival	Survival time was defined to be the length of time from start of study therapy to death due to any cause or until last follow-up (censored value).	3 years
Percentage of Participants With 2-year Disease-free Survival	Disease-free survival was defined as the time from start of study therapy to documentation of disease recurrence. Participants who died without documentation of recurrence were considered to have had tumor recurrence at the time of death unless there was documented evidence that no recurrence occured before death. Participants who failed to return for evaluation after beginning therapy were censored for recurrence on the last day of therapy. Participants who experienced major treatment violations were censored for recurrence on the date the treatment violation occured.	2 years
Number of Participants With Frequent (>=15% Grade 3/4 Incidence) Adverse Events Regardless of Attribution	Adverse events were assessed by NCI CTCAE (Common Terminology Criteria for Adverse Events) v3.0. Grade 1= mild, grade 2= moderate, grade 3= severe, grade 4= life-threatening; and grade 5= death.	Week 1, 3, 5, 7, 9, 4-6 weeks after therapy and within 30 days post surgery

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI); Amgen
• Investigators: Study Chair: A. Craig Lockhart, MD, Washington University School of Medicine

Publications and helpful links

General Publications

• Lockhart AC, Reed CE, Decker PA, Meyers BF, Ferguson MK, Oeltjen AR, Putnam JB, Cassivi SD, Montero AJ, Schefter TE; American College of Surgeons Oncology Group. Phase II study of neoadjuvant therapy with docetaxel, cisplatin, panitumumab, and radiation therapy followed by surgery in patients with locally advanced adenocarcinoma of the distal esophagus (ACOSOG Z4051). Ann Oncol. 2014 May;25(5):1039-44. doi: 10.1093/annonc/mdu091. Epub 2014 Feb 20. Erratum In: Ann Oncol. 2019 Feb 1;30(2):345.

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): November 1, 2011
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: September 22, 2008
• First Submitted That Met QC Criteria: September 22, 2008
• First Posted (Estimate): September 23, 2008

Study Record Updates

• Last Update Posted (Estimate): March 11, 2016
• Last Update Submitted That Met QC Criteria: February 10, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: stage II esophageal cancer; stage III esophageal cancer; adenocarcinoma of the esophagus; adenocarcinoma of the gastroesophageal junction; stage IV esophageal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Adenocarcinoma; Esophageal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Immunological; Docetaxel; Panitumumab
• Other Study ID Numbers: ACOSOG-Z4051; U10CA076001 (U.S. NIH Grant/Contract); CDR0000596674 (Registry Identifier: Physician Data Query); NCI-2009-00346 (Registry Identifier: NCI Clinical Trials Reporting Office)