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Epirubicin, Oxaliplatin and Fluorouracil (EOF) in Cancer of the Esophagus, Gastroesophageal Junction, or Stomach

Primary Purpose

Esophageal Cancer, Gastric Cancer

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

cisplatin

epirubicin hydrochloride

fluorouracil

oxaliplatin

adjuvant therapy

neoadjuvant therapy

About this trial

This is an interventional treatment trial for Esophageal Cancer focused on measuring adenocarcinoma of the esophagus, adenocarcinoma of the stomach, stage III esophageal cancer, stage IV esophageal cancer, stage III gastric cancer, stage IV gastric cancer, stage II esophageal cancer, stage II gastric cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients must have a histologic diagnosis of adenocarcinoma of the esophagus, gastroesophageal junction or gastric cardia, based on biopsy material or adequate cytologic exam.
Patients must be clinically staged according to the AJCC 2002 staging system and must have either T3-4, or N1 or M1a disease. Staging should include at least an upper endoscopy with endoscopic ultrasound and an FDG-PET/CT scan.
Patients must have an ECOG performance status of 0-1.
Patients must have adequate bone marrow function as evidenced by: Absolute neutrophil count > 1,500/uL Platelet count > 100,000/uL
Patients must have adequate renal function as evidenced by serum creatinine < 1.6 mg/dL
Patients must have adequate hepatic function as evidenced by:Serum total bilirubin < 1.5 mg/dL Alkaline phosphatase < 3X the institutional ULN AST/ALT < 3X the institutional ULN
Patients must have adequate pulmonary function as evidenced by an FEV1 > 50% predicted.
Patients or their legal representatives must be able to read, understand, provide and sign informed consent to participate in the trial.
Patients of childbearing potential 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)
Age > 18 years

Exclusion Criteria:

Patients with any other diagnosis except for adenocarcinoma (squamous cell carcinoma, small cell carcinoma, mixed adenosquamous, lymphoma, sarcoma etc,) will be ineligible.
Patients with any evidence of distant hematogenous or distant nodal disease (M1b) will be ineligible.
No prior chemotherapy, radiation therapy or surgery for this malignancy will be allowed. Prior endoscopic debulking, laser therapy or dilatation will not exclude a patient.
Patients with another active malignancy will not be eligible except for curatively treated basal cell carcinoma of the skin, cervical intra-epithelial neoplasia, or localized prostate cancer with a current PSA of < 1.0 mg/dL on 2 successive evaluations at least 3 months apart, with the most recent evaluation within 4 weeks of entry
Patients with an active infection will not be eligible.
Patients with known hypersensitivity to any of the components of oxaliplatin, epirubicin, fluorouracil or cisplatin will not be eligible.
Patients who are receiving any other 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) will not be eligible.
Patients with a baseline peripheral neuropathy greater than or equal Grade 2 will not be eligible.
Patients who are pregnant or lactating will not be eligible.
Patients with any other medical condition, including mental illness or substance abuse, deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results, will not be eligible.
Patients with any history of an allogeneic transplant will not be eligible.
Patients with known infection with HIV, Hepatitis B or C (active, previously treated or both) will not be eligible.

Sites / Locations

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Epirubicin, Oxaliplatin and Fluorouracil

Arm Description

Outcomes

Primary Outcome Measures

Feasibility of Induction Chemoradiotherapy as Measured by Resectability Rate

Feasibility of induction chemoradiotherapy as measured by resectability in greater than 75% of participants. The number of participants that were resectable.

Secondary Outcome Measures

Clinical Response Rate

Percent of participants with a clinical response: Complete clinical response is defined as the complete disappearance of all clinical evidence of tumor. Partial clinical response is defined as any improvement in the clinically determined T or N stage (without reciprocal deterioration in N or T) or a resolution of M1a disease, when compared to the pretreatment clinical stage. A partial response will not be defined based only on shrinkage of a measurable lesion unless there is improvement in the TNM stage. Stable clinical disease is defined as no change in the clinical TNM stage when compared to the pretreatment clinical stage. Progressive clinical disease is defined as any increase in the T or N stage irrespective of any reciprocal improvement in N or T, or as the development of new areas of malignancy or metastases.

Pathological Response Rate

Percent of participants with a clinical response: Complete pathologic response is defined as the complete disappearance of all viable tumor in the surgical specimen. Partial pathologic response is defined as any improvement in the pathologically determined T or N stage (without reciprocal deterioration in N or T) or a resolution of M1a disease, when compared to the pretreatment esophageal ultrasound-determined clinical stage. A partial response will not be defined based only on shrinkage of a measurable lesion unless there is improvement in the TNM stage. Stable pathologic disease is defined as no change in the pathologically determined TNM stage when compared to the pretreatment esophageal ultrasound. Progressive pathologic disease is defined as any increase in the T or N stage irrespective of any reciprocal improvement in N or T, or as the development of new areas of malignancy or metastases.

Overall Survival

Percent of participants with a 3-year survival. A survival rate greater than 50% would suggest efficacy and justify further study.

Locoregional Control and Distant Metastatic Control

A distant metastatic control rate of greater than 55 % would suggest efficacy for this treatment protocol. A locoregional control rate of less than 75% would suggest inefficacy. Locoregional control (LRC) defined by recurrence at the primary site or in regional lymph nodes and distant metastatic control (DMC), defined by recurrence in a distant site.

Postoperative Adjuvant Chemoradiotherapy Feasibility

Ability to complete postoperative chemoradiotherapy. A threshold level of 65% was set and if less than this percentage completed the phase, it would be deemed unacceptable. The anticipation was that 53-patients would be evaluable for this end point.

Full Information

NCT ID

NCT00601705

First Posted

January 23, 2008

Last Updated

April 18, 2019

Sponsor

Case Comprehensive Cancer Center

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT00601705

Brief Title

Epirubicin, Oxaliplatin and Fluorouracil (EOF) in Cancer of the Esophagus, Gastroesophageal Junction, or Stomach

Official Title

A Phase II Trial of Induction Chemotherapy With Epirubicin, Oxaliplatin and Fluorouracil (EOF) Followed by Esophagogastrectomy and Post-operative Concurrent Chemoradiotherapy With Fluorouracil and Cisplatin, in Patients With Loco-regionally Advanced Adenocarcinoma of the Esophagus, Gastroesophageal Junction and Gastric Cardia

Study Type

Interventional

2. Study Status

Record Verification Date

April 2019

Overall Recruitment Status

Completed

Study Start Date

January 5, 2008 (Actual)

Primary Completion Date

March 26, 2012 (Actual)

Study Completion Date

January 23, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Case Comprehensive Cancer Center

Collaborators

National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as epirubicin, oxaliplatin, fluorouracil, and cisplatin, 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 chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving chemotherapy and radiation therapy after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying how well giving combination chemotherapy, surgery, and radiation therapy works in treating patients with locoregionally advanced cancer of the esophagus, gastroesophageal junction, or stomach.

Detailed Description

OBJECTIVES: Primary To assess the feasibility and tolerability of induction chemotherapy comprising epirubicin hydrochloride, oxaliplatin, and fluorouracil (EOF), followed by surgical resection and postoperative concurrent chemoradiotherapy comprising fluorouracil and cisplatin in patients with locoregionally advanced adenocarcinoma of the esophagus, gastroesophageal junction, or gastric cardia. Secondary To determine the rate of complete and partial response to three courses of EOF induction chemotherapy. To compare the recurrence-free and overall survival of patients treated with this regimen vs historical controls at this institution. To compare patterns of failure in patients treated with this regimen vs historical controls at this institution. OUTLINE: Induction chemotherapy: Patients receive epirubicin hydrochloride IV over 3-15 minutes and oxaliplatin IV over 2 hours on day 1 and fluorouracil IV continuously on days 1-21. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Surgery: Four weeks after completion of induction chemotherapy, patients with locoregionally confined disease (T0-4, N0-1, M0-1a) undergo transthoracic esophagogastrectomy or total gastrectomy with Roux-en-Y esophagojejunostomy, depending on the location and extent of the tumor at the time of surgery. Postoperative chemoradiotherapy: Beginning 6-10 weeks after surgery, patients undergo radiotherapy 5 days a week for approximately 6 weeks. Patients also receive fluorouracil IV continuously and cisplatin IV continuously over 96 hours in weeks 1 and 4 of radiotherapy. After completion of study treatment, patients are followed every 8-12 weeks for 3 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Esophageal Cancer, Gastric Cancer

Keywords

adenocarcinoma of the esophagus, adenocarcinoma of the stomach, stage III esophageal cancer, stage IV esophageal cancer, stage III gastric cancer, stage IV gastric cancer, stage II esophageal cancer, stage II gastric cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

61 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Epirubicin, Oxaliplatin and Fluorouracil

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

cisplatin

Intervention Description

20 mg/m2/day IV continuous infusion over 24 hours for 96 total hours.

Intervention Type

Drug

Intervention Name(s)

epirubicin hydrochloride

Intervention Description

50 mg/m2 IV bolus

Intervention Type

Drug

Intervention Name(s)

fluorouracil

Intervention Description

200 mg/m2/day will be given as a continuous intravenous infusion for all 9 weeks, beginning on day 1.

Intervention Type

Drug

Intervention Name(s)

oxaliplatin

Intervention Description

130 mg/m2 IV infusion over 2 hours

Intervention Type

Procedure

Intervention Name(s)

adjuvant therapy

Intervention Description

Between 6-10 weeks after surgery patients will begin postoperative chemoradiotherapy. Daily radiation therapy fractions of 180-200 cGy will be given to the esophago-gastric bed and draining lymphatic regions to a total dose of 50-55 Gy (60 Gy in the event of an R1 or R2 resection). Concurrent with this radiation, two cycles of chemotherapy will be given, during the first and fourth weeks of the radiation

Intervention Type

Procedure

Intervention Name(s)

neoadjuvant therapy

Intervention Description

Three weeks after discontinuing the fluorouracil (12 weeks after study entry) patients will be fully restaged to assess for a clinical response, and to ensure that there is no contraindication to surgical resection, which will be scheduled for approximately one week later (13 weeks after study entry). Surgery will consist of a transthoracic esophagogastrectomy or a total gastrectomy with Roux-en-Y esophagojejunostomy depending on the location and extent of the tumor at surgery. An appropriate lymphadenectomy will be performed. Immediate reconstruction is anticipated if possible.

Primary Outcome Measure Information:

Title

Feasibility of Induction Chemoradiotherapy as Measured by Resectability Rate

Description

Feasibility of induction chemoradiotherapy as measured by resectability in greater than 75% of participants. The number of participants that were resectable.

Time Frame

at 12 weeks from on study

Secondary Outcome Measure Information:

Title

Clinical Response Rate

Description

Time Frame

at 12 weeks from on study

Title

Pathological Response Rate

Description

Time Frame

after completion of study at 35 weeks

Title

Overall Survival

Description

Percent of participants with a 3-year survival. A survival rate greater than 50% would suggest efficacy and justify further study.

Time Frame

at 3 years from on study

Title

Locoregional Control and Distant Metastatic Control

Description

Time Frame

at 3 years from on study

Title

Postoperative Adjuvant Chemoradiotherapy Feasibility

Description

Time Frame

Between 6 to 10 weeks postoperatively

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients must have a histologic diagnosis of adenocarcinoma of the esophagus, gastroesophageal junction or gastric cardia, based on biopsy material or adequate cytologic exam. Patients must be clinically staged according to the AJCC 2002 staging system and must have either T3-4, or N1 or M1a disease. Staging should include at least an upper endoscopy with endoscopic ultrasound and an FDG-PET/CT scan. Patients must have an ECOG performance status of 0-1. Patients must have adequate bone marrow function as evidenced by: Absolute neutrophil count > 1,500/uL Platelet count > 100,000/uL Patients must have adequate renal function as evidenced by serum creatinine < 1.6 mg/dL Patients must have adequate hepatic function as evidenced by:Serum total bilirubin < 1.5 mg/dL Alkaline phosphatase < 3X the institutional ULN AST/ALT < 3X the institutional ULN Patients must have adequate pulmonary function as evidenced by an FEV1 > 50% predicted. Patients or their legal representatives must be able to read, understand, provide and sign informed consent to participate in the trial. Patients of childbearing potential 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) Age > 18 years Exclusion Criteria: Patients with any other diagnosis except for adenocarcinoma (squamous cell carcinoma, small cell carcinoma, mixed adenosquamous, lymphoma, sarcoma etc,) will be ineligible. Patients with any evidence of distant hematogenous or distant nodal disease (M1b) will be ineligible. No prior chemotherapy, radiation therapy or surgery for this malignancy will be allowed. Prior endoscopic debulking, laser therapy or dilatation will not exclude a patient. Patients with another active malignancy will not be eligible except for curatively treated basal cell carcinoma of the skin, cervical intra-epithelial neoplasia, or localized prostate cancer with a current PSA of < 1.0 mg/dL on 2 successive evaluations at least 3 months apart, with the most recent evaluation within 4 weeks of entry Patients with an active infection will not be eligible. Patients with known hypersensitivity to any of the components of oxaliplatin, epirubicin, fluorouracil or cisplatin will not be eligible. Patients who are receiving any other 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) will not be eligible. Patients with a baseline peripheral neuropathy greater than or equal Grade 2 will not be eligible. Patients who are pregnant or lactating will not be eligible. Patients with any other medical condition, including mental illness or substance abuse, deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results, will not be eligible. Patients with any history of an allogeneic transplant will not be eligible. Patients with known infection with HIV, Hepatitis B or C (active, previously treated or both) will not be eligible.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

David J. Adelstein, MD

Organizational Affiliation

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44106-5065

Country

United States

12. IPD Sharing Statement

Learn more about this trial

Epirubicin, Oxaliplatin and Fluorouracil (EOF) in Cancer of the Esophagus, Gastroesophageal Junction, or Stomach

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