Oxaliplatin, Fluorouracil, Erlotinib Hydrochloride, and Radiation Therapy Before Surgery and Erlotinib Hydrochloride After Surgery in Treating Patients With Locally Advanced Cancer of the Esophagus or Gastroesophageal Junction

A Phase I Study of Preoperative Chemoradiation With Oxaliplatin, 5-Fluorouracil, Erlotinib and Radiation Followed by Resection and Consolidative Erlotinib for Patients With Locally Advanced Cancer of the Esophagus and Gastroesophageal Junction

This phase I trial is studying the side effects and best dose of erlotinib hydrochloride when given together with oxaliplatin, fluorouracil, and radiation before surgery and alone after surgery in treating patients with locally advanced cancer of the esophagus and gastroesophageal junction. Drugs used in chemotherapy, such as oxaliplatin and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving combination chemotherapy together with erlotinib hydrochloride and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving erlotinib hydrochloride after surgery may kill any tumor cells that remain after surgery

Study Overview

• Status: Completed
• Conditions: Adenocarcinoma of the Gastroesophageal Junction; Stage II Gastric Cancer; Stage III Gastric Cancer; Squamous Cell Carcinoma of the Esophagus; Adenocarcinoma of the Stomach; Adenocarcinoma of the Esophagus; Stage III Esophageal Cancer; Stage II Esophageal Cancer
• Intervention / Treatment: Drug: oxaliplatin; Drug: fluorouracil; Radiation: radiation therapy; Drug: erlotinib hydrochloride; Procedure: laboratory biomarker analysis; Other: immunohistochemistry staining method; Procedure: conventional surgery; Procedure: positron emission tomography; Procedure: computed tomography; Genetic: gene expression analysis; Radiation: fludeoxyglucose F 18

Detailed Description

OBJECTIVES:

I. The primary aim of this phase I study is to evaluate the safety of multi-drug chemotherapy (with the addition of an anti-epidermal growth factor receptor [EGFR] agent erlotinib [erlotinib hydrochloride]) and concomitant radiotherapy followed by resection and consolidative erlotinib for the treatment of locally advanced esophageal cancer as judged by the dose limiting toxicities. Correlative endpoints include an analysis of pre-treatment tumor cyclin D1 expression and EGFR expression/amplification.

III. Correlate pathologic complete response with changes in fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)-computed tomography (CT) - pre and post-chemoradiation.

OUTLINE: This is a dose escalation study of erlotinib hydrochloride

CHEMORADIOTHERAPY: Patients undergo radiation therapy once daily (QD), 5 days a week and receive fluorouracil intravenously (IV) continuously and erlotinib hydrochloride orally (PO) QD on days 1-38. Patients also receive oxaliplatin IV over 2 hours on days 1, 15, and 29.

SURGERY: Within 4-8 weeks after completion of chemoradiotherapy, patients with potentially resectable disease (i.e., complete response, partial response, or stable disease) undergo surgery to remove the tumor.

CONSOLIDATION CHEMOTHERAPY: Within 2-4 weeks after surgery, patients with tumors that demonstrate positive immunohistochemistry for EGFR and/or cyclin D1 (in the pretreatment biopsy or in the residual tumor in the esophagectomy specimen) receive consolidation chemotherapy comprising erlotinib hydrochloride PO QD for 12 weeks.

After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 2 years, and then annually thereafter.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences

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

Inclusion Criteria:

• Newly diagnosed patients with locally advanced esophageal cancer with either squamous or adenocarcinoma histology; patients should have evidence of extension of disease into or through the wall of the esophagus (T2-4) and/or regional nodal metastasis (N1)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Non-pregnant; patients of childbearing potential and their partners must agree to use an effective form of contraception during the study and for 90 days following the last dose of study medication (an effective form of contraception is an oral contraceptive or a double barrier method); nursing mothers are also ineligible
• Prior treatment: Greater than one week shall have elapsed since any major surgery; no prior chemotherapy or radiotherapy is allowed
• Adequate whole blood cell (WBC) and platelets (Plt) as determined by medical oncology
• Serum creatinine =< 1.5 mg/dl
• Creatinine clearance >= 60 ml/min
• Hemoglobin (Hgb) >= 9.0 gm/dl
• Absolute neutrophil count >= 1,500/uL
• Serum total bilirubin =< 1.5 mg/dL
• Alkaline phosphatase =< 3X the upper limit of normal (ULN) for the reference lab
• Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than 2X ULN for the reference laboratory
• Patients must be told of the investigational nature of the study and must sign a written informed consent
• No serious medical or psychiatric illnesses which would prevent informed consent or otherwise limit survival to less than two years; no history of refractory congestive heart failure or cardiomyopathy
• Patients should be evaluated by medical oncology, radiation oncology, and surgery, and felt to by all to be suitable for trimodality therapy

Exclusion Criteria:

Patients with an active infection or with a fever >= 38.5 degrees Celsius (C) within 3 days of the first scheduled day of protocol treatment

• History of prior malignancy within the past 5 years except for curatively treated basal cell carcinoma of the skin, cervical intra-epithelial neoplasia, or localized prostate cancer with a current prostate surface antigen (PSA) of < 1.0 mg/dL on 2 successive evaluations, at least 3 months apart, with the most recent evaluation no more than 4 weeks prior to entry
• Patients with known hypersensitivity to any of the components of oxaliplatin
• Patients who are receiving concurrent investigational therapy or who have received investigational therapy within 30 days of the first scheduled day of protocol treatment (investigational therapy is defined as treatment for which there is currently no regulatory authority approved indication)
• Peripheral neuropathy >= Grade 2
• History of allogeneic transplant
• Known human immunodeficiency virus (HIV) or Hepatitis B or C (active, previously treated or both)
• Pregnancy

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 (chemotherapy, enzyme inhibitor therapy); CHEMORADIOTHERAPY: Patients undergo radiation therapy QD, 5 days a week and receive fluorouracil IV continuously and erlotinib hydrochloride PO QD on days 1-38. Patients also receive oxaliplatin IV over 2 hours on days 1, 15, and 29. SURGERY: Within 4-8 weeks after completion of chemoradiotherapy, patients with potentially resectable disease (i.e., complete response, partial response, or stable disease) undergo surgery to remove the tumor. CONSOLIDATION CHEMOTHERAPY: Within 2-4 weeks after surgery, patients with tumors that demonstrate positive immunohistochemistry for EGFR and/or cyclin D1 (in the pretreatment biopsy or in the residual tumor in the esophagectomy specimen) receive consolidation chemotherapy comprising erlotinib hydrochloride PO QD for 12 weeks.

Drug: oxaliplatin; Given IV; Other Names: 1-OHP; Dacotin; Dacplat; Eloxatin; L-OHP; Drug: fluorouracil; Given IV; Other Names: 5-FU; 5-fluorouracil; 5-Fluracil; Radiation: radiation therapy; Undergo radiotherapy; Other Names: irradiation; radiotherapy; therapy, radiation; Drug: erlotinib hydrochloride; Given PO; Other Names: OSI-774; erlotinib; CP-358,774; Procedure: laboratory biomarker analysis; Correlative study; Other: immunohistochemistry staining method; Correlative study; Other Names: immunohistochemistry; Procedure: conventional surgery; Undergo surgical resection; Other Names: surgery, conventional; Procedure: positron emission tomography; Correlative study; Other Names: PET; FDG-PET; PET scan; tomography, emission computed; Procedure: computed tomography; Correlative study; Other Names: tomography, computed; Genetic: gene expression analysis; Correlative study; Radiation: fludeoxyglucose F 18; Undergo F18 PET and CT scan; Other Names: 18FDG; FDG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity rate of combination chemotherapy followed by surgery and erlotinib hydrochloride	Toxicity will be determined using the revised National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 3.0 for Toxicity and Adverse Event Reporting (CTCAE v3.0). The dose limiting toxicity will be defined as any of the following that can be attributal to therapy: Any grade 4 neutropenia and or any grade 4 thrombocytopenia, or any >= grade 3 non-hematologic toxicity that results in a greater than 3 day interruption of therapy.	Approximately 6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Time to progression	Approximately 4 years
Survival	Approximately 4 years
Specific characteristics that predict complete response rate (e.g., EGFR status, EGFR amplification, and cyclin D1 expression)	Over 4 years
Specific characteristics that predict complete response rate (e.g., EGFR status, EGFR amplification, and cyclin D1 expression)	Approximately 1 year
Test the predictive value of FDG-PET-CT imaging in identifying patients who will have a complete response	Approximately 1 year

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Collaborators: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2007
• Primary Completion (Actual): March 1, 2009
• Study Completion (Actual): March 1, 2009

Study Registration Dates

• First Submitted: February 14, 2012
• First Submitted That Met QC Criteria: March 21, 2012
• First Posted (Estimate): March 22, 2012

Study Record Updates

• Last Update Posted (Actual): July 2, 2018
• Last Update Submitted That Met QC Criteria: June 29, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• 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; Stomach Diseases; Head and Neck Neoplasms; Esophageal Diseases; Neoplasms, Squamous Cell; Carcinoma, Squamous Cell; Stomach Neoplasms; Adenocarcinoma; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Radiopharmaceuticals; Protein Kinase Inhibitors; Fluorodeoxyglucose F18; Erlotinib Hydrochloride; Fluorouracil; Oxaliplatin
• Other Study ID Numbers: IRB00007063; NCI-2009-01447 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); CCCWFU 60106 (Other Identifier: Wake Forest University Health Sciences)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No