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
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.
- 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
- 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
- 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