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Fluorouracil

Eniluracil

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Enzyme Inhibitors

Cola

776C85, 10mg/m2/dose, PO, Days 1-28 (BID), q 5 wk; 5-FU, 1.0mg/m2/dose, PO, Days 1-28 (BID), q 5 wk.

ethynyluracil

fluorouracil

Cynthia G. Leichman, MD

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Ethynyluracil may help fluorouracil kill more cancer cells by making tumor cells more sensitive to the drug.

PURPOSE: Phase II trial to study the effectiveness of fluorouracil plus ethynyluracil in treating patients with advanced colorectal cancer that has not responded to fluorouracil.

OBJECTIVES: I. Assess the confirmed response rate to fluorouracil (5-FU) plus ethynyluracil (776C85) in patients with metastatic colorectal cancer that has been demonstrated to be resistant to 5-FU. II. Assess time to progression and survival in this group of patients. III. Assess the frequency and severity of toxicities associated with this treatment.

OUTLINE: Patients are stratified according to relapse while receiving adjuvant therapy (relapse within 12 months of completing adjuvant therapy vs relapse while receiving adjuvant therapy). Patients receive oral doses of ethynyluracil (776C85) and fluorouracil twice daily for 28 days followed by 1 week of rest. Treatment continues every 5 weeks in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months the first year, every 4 months the second year, and every 6 months thereafter.

PROJECTED ACCRUAL: A total of 35-75 patients will be accrued for this study.

SWOG-S9635 Fluorouracil Plus Ethynyluracil in Advanced Colorectal Cancer Not Responded to Fluorouracil

A Phase II Trial of 5-Fluorouracil Plus 776C85 in Patients With Advanced Resistant Colorectal Cancer

To assess the confirmed response rate to 5-fluorouracil plus 776C85 in patients with measurable, disseminated colorectal cancer that has been demonstrated to be resistant to 5-fluorouracil.

To assess time to progression and survival in this group of patients.

To assess the frequency and severity of toxicities associated with this treatment.

National Cancer Institute (NCI)

SWOG Cancer Research Network

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Lymphoma

Lymphosarcoma

Micronutrients

Hematinics

Vitamins

Leucovorin

Antidotes

Protective Agents

Folic Acid

Vitamin B Complex

Trace Elements

Folate

Vitamin B9

5-Fluorouracil

Ethynyluracil

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.

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.

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

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Carcinoma

Carcinoma, Squamous Cell

Head and Neck Neoplasms

Nasopharyngeal Carcinoma

Mouth Neoplasms

Carcinoma, Adenoid Cystic

Laryngeal Diseases

Carcinoma, Verrucous

Carcinoma, Mucoepidermoid

Mucoepidermoid Tumor

Oral Cancer

Laryngeal Cancer

Hypopharyngeal Cancer

Adenoid Cystic Carcinoma

Lip and Oral Cavity Cancer

Mucoepidermoid Carcinoma

Antisickling Agents

Hydroxyurea

hydroxyurea

radiation therapy

Everett E. Vokes, MD

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining more than one chemotherapy drug with radiation therapy may kill more tumor cells.

PURPOSE: Phase I/II trial to study the effectiveness of combination chemotherapy plus radiation therapy in treating patients who have advanced mouth cancer.

OBJECTIVES: I. Assess the feasibility of the administration of ethynyluracil concurrently with fluorouracil and radiotherapy in patients with advanced oral cancer. II. Determine the maximum tolerated dose (MTD) and dose-limiting toxicities of this regimen in this patient population.

OUTLINE: This is a dose escalation study of fluorouracil and hydroxyurea. Patients receive oral ethynyluracil every 12 hours on days 1-7 and oral fluorouracil every 12 hours on days 2-6. Radiotherapy to the head and neck is administered twice daily on days 2-6. Treatment continues for 5-7 courses in the absence of unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of fluorouracil until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 3 of 6 patients experience dose limiting toxicities. Once the MTD of fluorouracil is determined, hydroxyurea is added to the treatment regimen. Patients receive fluorouracil and ethynyluracil as per the treatment schedule outlined above. Patients also receive oral hydroxyurea every 12 hours for 11 doses on days 1-6. Radiotherapy is administered as above. Cohorts of 3-6 patients receive escalating doses of hydroxyurea until the MTD is determined. Once the MTD of fluorouracil and hydroxyurea are determined, an additional 10 patients receive Phase II doses of ethynyluracil, fluorouracil and hydroxyurea as per the treatment schedule outlined above. Treatment continues in the absence of unacceptable toxicity. Patients are followed at 4-6 weeks, then every 6 months until death.

PROJECTED ACCRUAL: Approximately 40 patients will be accrued for this study over 2 years.

Combination Chemotherapy Plus Radiation Therapy in Treating Patients With Advanced Mouth Cancer

A Phase I Study of Concomitant Chemoradiotherapy With 776C85, 5-FU and Hydroxyurea for Patients With Poor Prognosis Oral Cancer

Robert H. Lurie Cancer Center

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
SWOG-S9635 Fluorouracil Plus Ethynyluracil in Advanced Colorectal Cancer Not Responded to Fluorouracil	NCT00003254	Colorectal Canc...	ethynyluracil fluorouracil	18 Years -	SWOG Cancer Research Network
A Phase I Trial of 5-Fluorouracil Given With 776C85 (GW776) and Low-Dose Leucovorin in Adult Patients With Solid Tumors	NCT00001579	Lymphoma Neoplasms	5-Fluorouracil Ethynyluracil Leucovorin	-	National Institutes of Health Clinical Center (CC)
SWOG-S9635 Fluorouracil Plus Ethynyluracil in Advanced Colorectal Cancer Not Responded to Fluorouracil	NCT00003254	Colorectal Canc...	ethynyluracil fluorouracil	18 Years -	SWOG Cancer Research Network
Combination Chemotherapy Plus Radiation Therapy in Treating Patients With Advanced Mouth Cancer	NCT00004901	Head and Neck C...	ethynyluracil fluorouracil hydroxyurea radiation thera...	18 Years -	National Cancer Institute (NCI)
Combination Chemotherapy Plus Radiation Therapy in Treating Patients With Advanced Mouth Cancer	NCT00004901	Head and Neck C...	ethynyluracil fluorouracil hydroxyurea radiation thera...	18 Years -	National Cancer Institute (NCI)
Combination Chemotherapy Plus Radiation Therapy in Treating Patients With Advanced Mouth Cancer	NCT00004901	Head and Neck C...	ethynyluracil fluorouracil hydroxyurea radiation thera...	18 Years -	National Cancer Institute (NCI)

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