FOLFOX-6 Induction Chemotherapy Followed by Esophagectomy and Post-operative Chemoradiotherapy in Patients With Esophageal Adenocarcinoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Case Comprehensive Cancer Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT02037048
First received: January 14, 2014
Last updated: July 21, 2014
Last verified: July 2014
  Purpose

This phase II trial studies how well oxaliplatin, leucovorin calcium, and fluorouracil followed by surgery and response based concurrent chemotherapy and radiation therapy works in treating patients with cancer of the esophagus, gastroesophageal junction, or gastric cardia. Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, fluorouracil, 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. Radiation therapy uses high energy x rays to kill tumor cells. Giving chemotherapy followed by surgery and response based chemotherapy and radiation therapy may kill more tumor cells.


Condition Intervention Phase
Adenocarcinoma of the Esophagus
Adenocarcinoma of the Gastroesophageal Junction
Adenocarcinoma of the Gastric Cardia
Stage IIIA Esophageal Cancer
Stage IIIB Esophageal Cancer
Stage IIIC Esophageal Cancer
Drug: oxaliplatin
Drug: leucovorin calcium
Drug: fluorouracil
Procedure: therapeutic conventional surgery
Radiation: radiation therapy
Drug: carboplatin
Drug: paclitaxel
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Trial of Modified FOLFOX-6 Induction Chemotherapy Followed by Esophagectomy and Post-operative Response Based Concurrent Chemoradiotherapy in Patients With Locoregionally Advanced Adenocarcinoma of the Esophagus, Gastro-esophageal Junction, and Gastric Cardia

Resource links provided by NLM:


Further study details as provided by Case Comprehensive Cancer Center:

Primary Outcome Measures:
  • Recurrence Free Survival (RFS) compared to historical averages [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Compare the number of study patients who achieved RFS with >50% remaining viable tumor after response adapted adjuvant chemoradiotherapy to historical data among patients with >50% viable tumor after induction chemotherapy. A once sided test (p<=0.05) will be used to describe significance of change.


Secondary Outcome Measures:
  • Symptomatic response [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Symptomatic response is defined as improvement in dysphagia by 1 grade from baseline. Level 1 - No dysphagia. Level 2 - Minimal dysphagia, able to swallow liquids and most solid foods, experiencing occasional difficulty. Level 3 - Moderate dysphagia, able to swallow liquids and very soft foods. Level 4 - Severe dysphagia, unable to swallow liquids or solids. Significance of change will be calculated using 95% confidence intervals.

  • Endoscopic response [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Complete response = no residual abnormality (cyT0N0-Stage 0). Partial response = any improvement in the clinically determined T or N stage (without reciprocal deterioration in T or N) when compared to the pretreatment clinical stage as assessed by EGD/EUS. Stable disease = no change in the clinical T or N stage when compared to the pretreatment assessment. Progressive disease = any increase in the T or N stage (irrespective of any reciprocal improvement in the T or N stage) when compared to the pretreatment clinical stage as assessed by EGD/EUS. Endoscopic response will be estimated using exact 95% confidence intervals.

  • Pathologic response [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    A positive pathologic response (+PR) will be defined as ≤ 50% residual tumor cells remaining. A negative pathologic response (-PR) will be defined as >50% residual tumor cells remaining. Pathologic response will be described using exact 95% confidence intervals.

  • Complete resection (R0) rate [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    R0 resection is defined as the resection of all gross and microscopic tumor. R0 resections will be estimated using exact 95% confidence intervals.

  • Incidence of toxicity [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Toxicities will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The number of toxicities will be estimated using exact 95% confidence intervals.

  • RFS within study patients [ Time Frame: Time from start of treatment until first recurrence or death from any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    RFS will be compared between patients with ≤ 50% and > 50% viable tumor using the log-rank test. Outcomes will be calculated relative to the start of therapy. Log rank tests will be used to estimate the hazard ratio for RFS for patients with > 50% viable tumor relative to those with ≤ 50%. If there are a sufficient number of events, multivariable Cox analysis will be done to adjust for other prognostic factors.

  • OS [ Time Frame: Time from start of treatment until death due to any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    OS will be compared between patients with ≤ 50% and > 50% viable tumor using the log-rank test. Outcomes will be calculated relative to the start of therapy. Log rank tests will be used to estimate the hazard ratio for OS for patients with > 50% viable tumor relative to those with ≤ 50%. If there are a sufficient number of events, multivariable Cox analysis will be done to adjust for other prognostic factors.

  • Rate of Distant Metastatic Control (DMC) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Kaplan Meier analysis will be used to estimate distant recurrence

  • Loco-regional control (LRC) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Kaplan-Meier analysis will be used to estimate local recurrence


Other Outcome Measures:
  • Change in circulating tumor cells (CTCs) [ Time Frame: Baseline to up to 2 months ] [ Designated as safety issue: No ]
    Change in the amount of CTCs before and after induction chemotherapy will be assessed using either the paired t-test or Wilcoxon signed rank test.

  • Change in Ki-67 expression [ Time Frame: Baseline to up to 2 months ] [ Designated as safety issue: No ]
    Change in Ki-67 expression before and after induction chemotherapy will be assessed using either the paired t-test or Wilcoxon signed rank test.

  • HER2 overexpression [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    HER2 overexpression will be described as frequency counts and percentages.

  • Prognostic effect of CTCs, Ki-67, and HER2 overexpression on pathologic response [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    The prognostic effect of CTCs, KI-67, and HER2 overexpression on pathologic response will be assessed with logistic regression analysis, and the prognostic effect on OS and RFS with Cox proportional hazards analysis.


Estimated Enrollment: 66
Study Start Date: January 2014
Estimated Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Positive Pathologic Response
Patients with ≤50% viable tumor cells remaining in the surgical specimen will receive postoperative chemo-radiotherapy with the mFOLFOX6 regimen
Drug: oxaliplatin
Given IV
Other Names:
  • 1-OHP
  • Dacotin
  • Dacplat
  • Eloxatin
  • L-OHP
Drug: leucovorin calcium
Given IV
Other Names:
  • CF
  • CFR
  • LV
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
Procedure: therapeutic conventional surgery
Undergo therapeutic conventional surgery
Radiation: radiation therapy
Undergo radiation therapy
Other Names:
  • irradiation
  • radiotherapy
  • therapy, radiation
Experimental: Negative Pathologic Response
Patients with >50% viable tumor cells remaining in the surgical specimen, will receive postoperative chemo-radiotherapy with weekly carboplatin and paclitaxel.
Drug: oxaliplatin
Given IV
Other Names:
  • 1-OHP
  • Dacotin
  • Dacplat
  • Eloxatin
  • L-OHP
Drug: leucovorin calcium
Given IV
Other Names:
  • CF
  • CFR
  • LV
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
Procedure: therapeutic conventional surgery
Undergo therapeutic conventional surgery
Radiation: radiation therapy
Undergo radiation therapy
Other Names:
  • irradiation
  • radiotherapy
  • therapy, radiation
Drug: carboplatin
Given IV
Other Names:
  • Carboplat
  • CBDCA
  • JM-8
  • Paraplat
  • Paraplatin
Drug: paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • TAX
  • Taxol

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have a histologic diagnosis of adenocarcinoma of the esophagus, GEJ, or GC based on biopsy material or adequate cytologic exam; tumors of the GC are defined as originating within 5 cm of the GEJ
  • Patients must be clinically staged according to the 7th edition (2010) of the American Joint Committee on Cancer (AJCC) staging system and must have either clinical T3-4a, or >= N1 disease; staging should include upper endoscopy with endoscopic ultrasound and a fludeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) scan (with diagnostic CT abdomen/pelvis preferred)
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  • Absolute neutrophil count >= 1,500/ul
  • Platelet count >=100,000/ul
  • Serum creatinine (Scr) =< 1.5mg/dl; if the Scr > 1.5, patients may still be eligible if the calculated glomerular filtration rate (GFR) (Cockroft-Gault) is >= 40ml/minute
  • Serum total bilirubin =< 1.5X the institutional upper limit of normal (ULN)
  • Alkaline phosphatase =< 3X the institutional ULN
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3X the institutional ULN
  • Patients with Gilbert's syndrome are eligible provided the total bilirubin is =< 3 and the remainder of the liver function tests (ALT, AST, alkaline phosphatase [ALK Phos]) are within the institutional normal range
  • Patients must have a forced expiratory volume in one second (FEV-1) and diffusing capacity of the lung for carbon monoxide (DLCO) > 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 must agree to use an effective form of contraception during this study and for 90 days following the last dose of chemotherapy; an effective form of contraception is an oral contraceptive or a double barrier method

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 evidence of clinical T4b (unresectable) or M1 (distant metastasis) according to the AJCC 2010 staging system will be ineligible
  • No prior chemotherapy, radiation therapy, or surgery for this malignancy will be allowed; prior endoscopic procedures for superficial disease (endoscopic mucosal resection, cryotherapy, photodynamic therapy, etc.) will not exclude a patient; prior dilatation is also allowed
  • Patients with another active malignancy will not be eligible except for:

    • Resected basal cell carcinoma and squamous cell carcinoma of the skin, cervical or prostatic intraepithelial neoplasia, and ductal or lobular carcinoma in situ of the breast
    • Patients with localized prostate cancer who have received curative intent therapy are also eligible provided:

      • Surgically treated patients have an undetectable prostate specific antigen (PSA)
      • Patients treated with brachytherapy have a PSA within the institutional normal range
      • Patients who have received pelvic external beam radiotherapy are not eligible
  • Patients with a clinically apparent active infection will not be eligible (please note, an isolated elevation in the white blood cell count, by itself, does not constitute evidence of an infection)
  • Patients with known hypersensitivity to any component of the chemotherapy regimen will not be eligible
  • Patients with a baseline peripheral neuropathy >= grade 2 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 as defined as treatment for which there is currently no regulatory authority approved indication) will not be eligible
  • Patients who are pregnant or lactating will not be eligible; pregnant patients are ineligible
  • Patients with angina, a cardiac ejection fraction < 50%, or ischemic heart disease are not eligible
  • Patients with any other medical condition, including mental illness or substance abuse, deemed by the investigator to be likely to interfere with the 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 solid organ or bone marrow transplant will not be eligible
  • Patients with a known history of infection with hepatitis B or hepatitis C virus (active, previously treated, or both) will not be eligible due to the increased risk of hepatotoxicity and viral reactivation associated with systemic chemotherapy
  • Patients with known infection with human immunodeficiency virus (HIV) will not be eligible
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02037048

Locations
United States, Ohio
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center Recruiting
Cleveland, Ohio, United States, 44106-5065
Contact: Michael J. McNamara    216-444-5110    mcnamam@ccf.org   
Principal Investigator: Michael J. McNamara         
Sponsors and Collaborators
Case Comprehensive Cancer Center
Investigators
Principal Investigator: Michael McNamara Case Comprehensive Cancer Center
  More Information

No publications provided

Responsible Party: Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT02037048     History of Changes
Other Study ID Numbers: CASE6213, NCI-2013-02492, CASE 6213, P30CA043703
Study First Received: January 14, 2014
Last Updated: July 21, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Esophageal Neoplasms
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Fluorouracil
Oxaliplatin
Carboplatin
Paclitaxel
Leucovorin
Levoleucovorin
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Vitamin B Complex
Vitamins

ClinicalTrials.gov processed this record on August 18, 2014