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

July 14, 2006 updated by: National Cancer Institute (NCI)

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

Enrollment

50

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Cancer Institute (NCI)

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

DISEASE CHARACTERISTICS:

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.

PRIOR/CURRENT THERAPY:

BIOLOGIC THERAPY:

No immunotherapy within past 4 weeks.

Recovered from toxic effects.

CHEMOTHERAPY:

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

No mitomycin within past 12 weeks.

Recovered from toxic effects.

ENDOCRINE THERAPY: Not specified.

RADIOTHERAPY:

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

Recovered from toxic effects.

SURGERY: Recovered from prior surgery.

OTHER: No concurrent cimetidine.

PATIENT CHARACTERISTICS:

AGE: 18 and over.

PERFORMANCE STATUS: ECOG 0-2.

LIFE EXPECTANCY: Not specified.

HEMATOPOIETIC:

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

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

HEPATIC:

Bilirubin no greater than 2 times upper normal limit;

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

RENAL:

Creatinine no greater than 1.6 mg/dL;

Creatinine clearance greater than 55 mL/min.

OTHER:

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 1997

Primary Completion

December 7, 2022

Study Completion

March 1, 2001

Study Registration Dates

First Submitted

November 3, 1999

First Submitted That Met QC Criteria

December 9, 2002

First Posted (Estimate)

December 10, 2002

Study Record Updates

Last Update Posted (Estimate)

July 17, 2006

Last Update Submitted That Met QC Criteria

July 14, 2006

Last Verified

May 1, 2000

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 970136
  • 97-C-0136

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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