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


Phase 1
N/A
N/A
Not Enrolling
Both
Lymphoma, Neoplasms

Thank you

Trial Information

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


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.

Inclusion Criteria


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.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Primary Purpose: Treatment

Authority:

United States: Federal Government

Study ID:

970136

NCT ID:

NCT00001579

Start Date:

June 1997

Completion Date:

March 2001

Related Keywords:

  • Lymphoma
  • Neoplasms
  • Biochemical Modulation
  • Dihydropyrimidine Dehydrogenase
  • Oral Administration
  • Pharmacokinetics
  • Neoplasms
  • Lymphoma

Name

Location

National Cancer Institute (NCI)Bethesda, Maryland  20892