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

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Terminated

CT.gov ID

NCT00002796

Collaborator

(none)

Enrollment

Location

Arm

Study Details

Study Description

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:

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.
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).

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

Study Type:

Interventional

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 1, 1997

Actual Primary Completion Date :

Dec 1, 2004

Arms and Interventions

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

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

Primary Outcome Measures

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) [1 week]
Efficacy of FU in combination with PB, indomethacin and rhIFNg in patients with advanced colorectal cancer (Phase II) [Up to 7 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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