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Phase I-II Study of Fluorouracil in Combination With Phenylbutyrate in Advanced Colorectal Cancer

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ClinicalTrials.gov Identifier: NCT00002796
Recruitment Status : Terminated (Administratively complete.)
First Posted : January 27, 2003
Last Update Posted : February 1, 2013
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
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Brief Summary:
Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Interferon-gamma may interfere with the growth of tumor cells and slow the growth of the tumor. Combining more than one drug with interferon-gamma may kill more tumor cells. This phase I/II trial is studying the side effects and best dose of giving fluorouracil together with phenylbutyrate, indomethacin, and interferon-gamma and to see how well it works in treating patients with stage IV colorectal cancer

Condition or disease Intervention/treatment Phase
Mucinous Adenocarcinoma of the Colon Mucinous Adenocarcinoma of the Rectum Recurrent Colon Cancer Recurrent Rectal Cancer Signet Ring Adenocarcinoma of the Colon Signet Ring Adenocarcinoma of the Rectum Stage IVA Colon Cancer Stage IVA Rectal Cancer Stage IVB Colon Cancer Stage IVB Rectal Cancer Drug: fluorouracil Drug: sodium phenylbutyrate Drug: indomethacin Biological: recombinant interferon gamma Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine in a Phase I study the toxicity of flurouracil (FU) when given in escalating doses in combination with fixed doses of phenlylbutyrate (PB), indomethacin and recombinant human interferon-gamma (rhIFNg) to patients with advanced colorectal cancer.

II. To determine in a Phase II study the efficacy of FU in combination with PB, indomethacin and rhIFNg in patients with advanced colorectal cancer.

OUTLINE: This is a dose-escalation study of fluorouracil (5-FU).

Phase I: Patients receive 5-FU IV over 24 hours on day 1; phenylbutyrate IV over 120 hours and oral indomethacin daily on days 2-6; and interferon gamma subcutaneously on days 2, 4, and 6. Courses repeat weekly in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of 5-FU until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which less than 2 of 6 patients experience dose-limiting toxicity (DLT).

Phase II :Patients receive 5-FU, phenylbutyrate, indomethacin, and interferon gamma as in phase I at the MTD.

Patients are followed for survival.

PROJECTED ACCRUAL: A maximum of 24 patients will be accrued for the phase I portion of this study and approximately 46 patients will be accrued for the phase II portion of this study.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 46 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I-II Study of Fluorouracil in Combination With Phenylbutyrate, Indomethacin and Recombinant Human Interferon-Gamma in Advanced Colorectal Cancer
Study Start Date : May 1997
Actual Primary Completion Date : December 2004

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Treatment (fluorouracil, phenylbutyrate, indomethacin, IFN-G

Phase I: Patients receive 5-FU IV over 24 hours on day 1; phenylbutyrate IV over 120 hours and oral indomethacin daily on days 2-6; and interferon gamma subcutaneously on days 2, 4, and 6. Courses repeat weekly in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of 5-FU until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which less than 2 of 6 patients experience dose-limiting toxicity (DLT).

Phase II: Patients receive 5-FU, phenylbutyrate, indomethacin, and interferon gamma as in phase I at the MTD.

 Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU

Drug: sodium phenylbutyrate
Given IV
Other Names:
  • Buphenyl
  • sodium 4-phenylbutyrate

Drug: indomethacin
Given orally
Other Names:
  • INDO
  • Indocin
  • Indometacin

Biological: recombinant interferon gamma
Given subcutaneously
Other Names:
  • Actimmune
  • gamma interferon
  • IFN-G


Outcome Measures
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Primary Outcome Measures :
  1. Toxicity of flurouracil (FU) when given in escalating doses in combination with fixed doses of phenlylbutyrate (PB), indomethacin and recombinant human interferon-gamma (rhIFNg) to patients with advanced colorectal cancer (Phase I) [ Time Frame: 1 week ]
  2. Efficacy of FU in combination with PB, indomethacin and rhIFNg in patients with advanced colorectal cancer (Phase II) [ Time Frame: Up to 7 years ]

Eligibility Criteria
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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Stage IV colorectal adenocarcinoma, excluding brain metastases
  • Histological confirmation of colorectal adenocarcinoma
  • Previously untreated patients

  • Previously treated patients

    • For the Phase I trial, no limitations
    • For the Phase II trial, previous treated limited to adjuvant radiation and/or chemotherapy which is completed at least 12 months before documentation of metastatic disease; patients may not have received chemotherapy for metastatic disease
  • For the Phase I trial, patients may have measurable disease or unmeasurable disease; for the Phase II trial, patients must have measurable disease in at least two dimensions on x-rays, CT scan or MRI
  • Expected survival of at least 16 weeks
  • Performance status of >= 70% (Karnofsky)
  • WBC >= 3000 uL
  • Platelet count >= 100,000/uL
  • Bilirubin =< 2 x ULN
  • Creatinine =< 2 x ULN
  • Not pregnant and not lactating; women of child bearing age must have negative pregnancy test (beta-hcg)
  • No allergies to interferon-gamma or E.coli derived products
  • No serious medical intercurrent medical illnesses, including Class III or IV cardiovascular disease; patient may not be dependent on immunosuppressive drugs including corticosteroids, and may not receive these drugs for the entire duration of the study
  • No diarrhea, and with adequate oral intake
  • Patients of child-bearing age and potential must agree to use adequate birth control other than oral contraceptives for the entire duration of the study
  • No previous or concurrent malignancy except inactive nonmelanoma skin cancer, in situ carcinoma of the cervix, grade 1 bladder cancer, or other cancers if the patient has been disease free for >= 5 years
  • Patients must be oriented and rational, and aware of the investigational nature of the study
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00002796


Locations
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United States, New York
Mount Sinai Medical Center
New York, New York, United States, 10029
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Max Sung Icahn School of Medicine at Mount Sinai
More Information
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00002796    
Obsolete Identifiers: NCT01925326
Other Study ID Numbers: NCI-2013-00038
96-322 ME*
CDR0000064879 ( Registry Identifier: PDQ (Physician Data Query) )
First Posted: January 27, 2003    Key Record Dates
Last Update Posted: February 1, 2013
Last Verified: January 2013
Additional relevant MeSH terms:
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Adenocarcinoma
Rectal Neoplasms
Colonic Neoplasms
Adenocarcinoma, Mucinous
Cystadenocarcinoma
Recurrence
Disease Attributes
Pathologic Processes
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
 Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Cystic, Mucinous, and Serous
Interferons
Interferon-gamma
Indomethacin
Fluorouracil
4-phenylbutyric acid
Antimetabolites
Molecular Mechanisms of Pharmacological Action