CHFR Methylation Status Esophageal Cancer Study (J10130)

A Phase 2 Study of Paclitaxel With Cisplatin Versus Fluoropyrimidine With a Platinum Agent for Neoadjuvant Therapy in Operable Esophageal Cancer Based on CHFR Methylation Status in Diagnostic Biopsies

This is a Phase 2 Study of Paclitaxel with Cisplatin versus Fluoropyrimidine with a Platinum Agent for Neoadjuvant Therapy in Operable Esophageal Cancer Based on CHFR Methylation Status in Diagnostic Biopsies.

Study Overview

• Status: Terminated
• Conditions: Esophageal Cancer
• Intervention / Treatment: Drug: Paclitaxel; Drug: Cisplatin; Radiation: Radiotherapy; Procedure: Esophagectomy; Drug: Oxaliplatin; Drug: 5-Fluorouracil

Detailed Description

Primary Objectives

• To determine the rate of pathological complete response when the inclusion of paclitaxel in neoadjuvant therapy is based on the presence or absence of CHFR methylation in diagnostic biopsy specimens.

Secondary Objectives

• To determine the survival outcome with this treatment strategy.
• To determine time to disease progression with this treatment strategy.
• To determine the agreement between tumor CHFR methylation and detection in plasma.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Ronan Kelly, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Histologically confirmed adenocarcinoma of the esophagus or GE junction
2. Patient must be untreated with chemotherapy, radiation therapy, or surgery for this diagnosis of esophageal cancer. (Endoscopy with biopsy and dilation is permitted.)
3. Tumor must be located between 20 cm from the teeth endoscopically and 2 cm into the gastric cardia. Cervical esophageal cancers and true gastric cancers are excluded.
4. Stage T2-3/N0-3/M0 as determined by imaging studies and biopsy where appropriate. T4 disease is permitted if defined as resectable by the thoracic surgeon (involvement of the pleura, pericardium or diaphragm).
5. Patients must have had an endoscopic ultrasound
6. Patients must have had a staging PET scan
7. Age ≥ 18 and ≤ 75
8. ECOG performance status 0-1.
9. Surgically resectable tumor
10. Patients with a history of a curatively treated malignancy must be disease-free and have a survival prognosis that exceeds three years.

11. Patients must have adequate organ and marrow function as defined below:

    • absolute neutrophil count ≥ 1,000/mcL
    • platelets ≥ 100,000/mcL
    • total bilirubin ≤ 2 mg/dL
    • AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional ULN
    • creatinine < 1.5 X institutional ULN
12. Female patients must not be pregnant or breast feeding. Radiotherapy is associated with significant birth defects and/or non-viable fetus. Paclitaxel, cisplatin, oxaliplatin, and 5-fluorouracil have teratogenic potential. A negative pregnancy test is required within 14 days of treatment for all women of childbearing potential. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, the patient should inform the treating physician immediately.
13. Patients must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients may not be receiving any investigational agents.
2. Incomplete healing from previous major surgery.
3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents they are assigned to.
4. Concomitant use of phenytoin, carbamazepine, barbiturates, rifampicin, phenobarbital, or St John's Wort; these drugs induce CYP3A and may decrease levels paclitaxel. 5-FU is a strong CYP2C9 inducer, and concomitant use with carvedilol, celecoxib, fosphenytoin, fluoxetine, phenytoin, warfarin and other CYP2C9 substrates should be used with caution.
5. Uncontrolled, inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
6. HIV-positive patients on combination antiretroviral therapy are ineligible because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
7. Patients from whom biopsy tissue cannot be obtained for correlate study analysis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A; Paclitaxel with Cisplatin along with Radiotherapy and followed by Esophagectomy	Drug: Paclitaxel; Paclitaxel 50 mg/m² (1 hr) days 1, 8, 15, 22, 29.; Other Names: Taxol; Abraxane; Drug: Cisplatin; Paclitaxel and cisplatin: Paclitaxel 50 mg/m² (1 hr) days 1, 8, 15, 22, 29.; Cisplatin 30 mg/m² days 1, 8, 15, 22, 29. Cisplatin and 5-fluorouracil: 5-Fluorouracil 1000 mg/m2 per day over 24 hours days 1- 4 and 29 - 32.; Cisplatin 75 mg/m² days 1, 29.; Other Names: Platinol; Radiation: Radiotherapy; Patients will be treated 5 days/week at 1.8 Gy/day to a total dose of 45Gy.; Other Names: IMRT; Procedure: Esophagectomy; The type of resection (Ivor-Lewis, Transhiatal, etc.) will be left to the discretion of the operating surgeon. Resection will be completed between 5 and 8 weeks starting from the completion of chemotherapy and radiation (days 36 - 56).; Other Names: Resection
Active Comparator: Arm B; Cisplatin or Oxaliplatin with 5-Fluorouracil along with Radiotherapy and followed by Esophagectomy	Drug: Cisplatin; Paclitaxel and cisplatin: Paclitaxel 50 mg/m² (1 hr) days 1, 8, 15, 22, 29.; Cisplatin 30 mg/m² days 1, 8, 15, 22, 29. Cisplatin and 5-fluorouracil: 5-Fluorouracil 1000 mg/m2 per day over 24 hours days 1- 4 and 29 - 32.; Cisplatin 75 mg/m² days 1, 29.; Other Names: Platinol; Radiation: Radiotherapy; Patients will be treated 5 days/week at 1.8 Gy/day to a total dose of 45Gy.; Other Names: IMRT; Procedure: Esophagectomy; The type of resection (Ivor-Lewis, Transhiatal, etc.) will be left to the discretion of the operating surgeon. Resection will be completed between 5 and 8 weeks starting from the completion of chemotherapy and radiation (days 36 - 56).; Other Names: Resection; Drug: Oxaliplatin; Oxaliplatin 85 mg/m2 days 1, 15, 29.; Other Names: Eloxatin; Drug: 5-Fluorouracil; Oxaliplatin and 5-fluorouracil: Oxaliplatin 85 mg/m2 days 1, 15, 29.; 5-Fluorouracil 180 mg/m2 prolonged infusion starting day 1 of radiation and completing on the final day of radiation (up to 40 days) Cisplatin and 5-fluorouracil: 5-Fluorouracil 1000 mg/m2 per day over 24 hours days 1-4 and 29-32.; Cisplatin 75 mg/m² days 1, 29.; Other Names: 5-FU; Carac; Adrucil; Fluorouracil; Efudex
Active Comparator: Arm C; Cisplatin with 5-Fluorouracil along with Radiotherapy and followed by Esophagectomy	Drug: Cisplatin; Paclitaxel and cisplatin: Paclitaxel 50 mg/m² (1 hr) days 1, 8, 15, 22, 29.; Cisplatin 30 mg/m² days 1, 8, 15, 22, 29. Cisplatin and 5-fluorouracil: 5-Fluorouracil 1000 mg/m2 per day over 24 hours days 1- 4 and 29 - 32.; Cisplatin 75 mg/m² days 1, 29.; Other Names: Platinol; Radiation: Radiotherapy; Patients will be treated 5 days/week at 1.8 Gy/day to a total dose of 45Gy.; Other Names: IMRT; Procedure: Esophagectomy; The type of resection (Ivor-Lewis, Transhiatal, etc.) will be left to the discretion of the operating surgeon. Resection will be completed between 5 and 8 weeks starting from the completion of chemotherapy and radiation (days 36 - 56).; Other Names: Resection; Drug: 5-Fluorouracil; Oxaliplatin and 5-fluorouracil: Oxaliplatin 85 mg/m2 days 1, 15, 29.; 5-Fluorouracil 180 mg/m2 prolonged infusion starting day 1 of radiation and completing on the final day of radiation (up to 40 days) Cisplatin and 5-fluorouracil: 5-Fluorouracil 1000 mg/m2 per day over 24 hours days 1-4 and 29-32.; Cisplatin 75 mg/m² days 1, 29.; Other Names: 5-FU; Carac; Adrucil; Fluorouracil; Efudex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response	CHFR methylation status correlates with response to taxane containing platinum-based combination therapy and tumor response involving operable Esophageal Cancer. Perform analysis comparing detection of CHFR in tumor and plasma.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival	Overall survival with given treatment strategy.	3 years
Time to Disease Progression	To determine time to disease progression with this treatment strategy.	3 years
Esophageal Tumor CHFR Methylation and Detection in Plasma	To determine the agreement between tumor CHFR methylation and detection in plasma.	3 years

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Ronan Kelly, M.D., Johns Hopkins University

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): June 1, 2014
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: June 9, 2011
• First Submitted That Met QC Criteria: June 10, 2011
• First Posted (Estimate): June 13, 2011

Study Record Updates

• Last Update Posted (Actual): January 25, 2019
• Last Update Submitted That Met QC Criteria: January 23, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Operable; Based on CHFR Methylation Status; Diagnostic Biopsies
• 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel; Cisplatin; Fluorouracil; Oxaliplatin
• Other Study ID Numbers: J10130; NA_00042668 (Other Identifier: JHMIRB); R33CA127055 (U.S. NIH Grant/Contract)