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

National Cancer Institute (NCI)

Status and phase: Terminated; Phase 2; Phase 1

Conditions: Stage IVB Colon Cancer; Stage IVA Rectal Cancer; Recurrent Colon Cancer; Signet Ring Adenocarcinoma of the Colon; Stage IVB Rectal Cancer; Mucinous Adenocarcinoma of the Rectum; Signet Ring Adenocarcinoma of the Rectum; Mucinous Adenocarcinoma of the Colon; Stage IVA Colon Cancer; Recurrent Rectal Cancer

Treatments: Drug: indomethacin; Drug: sodium phenylbutyrate; Biological: recombinant interferon gamma; Drug: fluorouracil

Study type: Interventional

Funder types: NIH

Identifiers

NCT00002796

NCI-2013-00038

96-322 ME*

CDR0000064879 (Registry Identifier)

Details and patient eligibility

About

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

Full 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.

Enrollment: 46 patients

Sex: All

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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46 participants in 1 patient group

Treatment (fluorouracil, phenylbutyrate, indomethacin, IFN-G

Experimental group

Description:

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.

Treatment:

Drug: fluorouracil

Biological: recombinant interferon gamma

Drug: sodium phenylbutyrate

Drug: indomethacin