A Phase I Trial of 5-Fluorouracil Given With 776C85 (GW776) and Low-Dose Leucovorin in Adult Patients With Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00001579
Recruitment Status : Completed
First Posted : December 10, 2002
Last Update Posted : July 17, 2006
Information provided by:
National Institutes of Health Clinical Center (CC)

Brief Summary:

This is a dose escalation study.

During the first period of this study, an initial pharmacological assessment of fluorouracil administered intravenously along with oral leucovorin calcium is made. Leucovorin calcium is given orally bid on days 1-3. Fluorouracil is given as a 24 hour infusion on day 2.

After a 2 week rest period and resolution of any toxicities experienced during the first period of treatment, patients are given an escalating dose of fluorouracil with fixed doses of leucovorin calcium and ethynyluracil. Ethynyluracil and leucovorin calcium are given bid orally on days 1-3 of each week. Fluorouracil is given bid orally on day 2 of each week. Treatment is repeated for three weeks followed by a one week rest period.

3 to 6 patients are enrolled at each dose level. Dose escalation proceeds until the maximum tolerated dose (MTD) is determined. MTD is defined as the dose preceding that at which 2 or more patients experience dose limiting toxicity.

Condition or disease Intervention/treatment Phase
Lymphoma Neoplasms Drug: 5-Fluorouracil Drug: Ethynyluracil Drug: Leucovorin Phase 1

Detailed Description:

The primary purpose of this Phase I protocol is to develop an orally administered regimen of fluorouracil (5-FU) given with fixed doses of leucovorin (LV) and 776C85 (GW776), a mechanism-based inhibitor of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme involved in the catabolism of 5-FU. In the presence of 776C85, 5-FU is cleared by renal mechanisms. The schedule employed is intended to mimic the pharmacologic profile associated with a 24 hour weekly continuous infusion of 5-FU without the need for an indwelling central venous catheter. The target population is adult cancer patients with solid tumors.

The first week, each patient will receive a single dose of 5-FU given by 24 hour continuous IV infusion at its recommended Phase II dose with low-dose oral LV. In the third week, the patient will begin 776C85 (GW776) and LV PO on days 1, 2, 3 at fixed doses. Oral 5-FU will be given on day 2, and the dose will be escalated in successive cohorts of patients. Treatment will be repeated weekly for three weeks, followed by a one week break. The dose of 5-FU will be adjusted according to individual tolerance. Cohorts of three patients will be entered at each dose level of 5-FU, which will be escalated until dose-limiting toxicity is seen (guidelines are outlined in the following schema). Treatment will be continued indefinitely until evidence of disease progression, provided the patient is tolerating therapy and wishes to continue.

Biochemical monitoring suggests that there is profound and sustained inhibition of DPD with a single dose of 20 mg PO 776C85 days 1-3 each week for three of four weeks. Once the MTD has been defined for the once daily dosing on days 1, 2, 3 schedule, a simplified schedule will be evaluated in which a single dose of 776C85 on day 1 in the evening, with oral leucovorin days 1 and 2, and 5-FU given day 2 as a single dose.

Since the pharmaceutical company has decided to go with a combined tablet of eniluracil/5-FU for future studies, the new schedule will be oral leucovorin on days 1 & 2, with 776C85 and 5-FU both given day 2 as a single dose.

Study Type : Interventional  (Clinical Trial)
Enrollment : 50 participants
Primary Purpose: Treatment
Official Title: A Phase I Trial of 5-Fluorouracil Given With 776C85 (GW776) and Low-Dose Leucovorin in Adult Patients With Solid Tumors
Study Start Date : June 1997
Study Completion Date : March 2001

Resource links provided by the National Library of Medicine

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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


Histologically proven solid tumor that has failed standard therapy or for which no such therapy exists.

Tumor may be locally advanced and unresectable, recurrent and/or metastatic.

Lymphomas with minimal or no involvement of bone marrow are also eligible.

No primary malignancies or metastatic disease of the CNS.

No symptomatic pre-existing peripheral neuropathy.



No immunotherapy within past 4 weeks.

Recovered from toxic effects.


No chemotherapy within past 4 weeks (6 weeks for nitrosoureas).

No mitomycin within past 12 weeks.

Recovered from toxic effects.



No radiotherapy within past 2 weeks (8 weeks for strontium therapy).

Recovered from toxic effects.

SURGERY: Recovered from prior surgery.

OTHER: No concurrent cimetidine.


AGE: 18 and over.


LIFE EXPECTANCY: Not specified.


Absolute granulocyte count at least 2000/mm(3);

Platelet count at least 100,000/mm(3).


Bilirubin no greater than 2 times upper normal limit;

SGOT/SGPT no greater than 4 times upper normal limit.


Creatinine no greater than 1.6 mg/dL;

Creatinine clearance greater than 55 mL/min.


Not pregnant or nursing.

Fertile patients must use effective contraception.

Not HIV positive.

No active infections requiring intravenous antibiotic therapy.

No other serious concurrent illness.

No evidence of hemolytic uremic syndrome.

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 identifier (NCT number): NCT00001579

United States, Maryland
National Cancer Institute (NCI)
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)

Publications: Identifier: NCT00001579     History of Changes
Other Study ID Numbers: 970136
First Posted: December 10, 2002    Key Record Dates
Last Update Posted: July 17, 2006
Last Verified: May 2000

Keywords provided by National Institutes of Health Clinical Center (CC):
Biochemical Modulation
Dihydropyrimidine Dehydrogenase
Oral Administration

Additional relevant MeSH terms:
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Enzyme Inhibitors