Both UFT (uracil and tegafur) and leucovorin combinations,[1,2] as
well as paclitaxel (Taxol),[3-5] are known to be effective as single
agents in heavily pretreated patients with a variety of solid tumor
malignancies. Oral UFT plus oral leucovorin (a combination being
developed under the trade name Orzel) provide activity comparable to
that of intravenously administered fluorouracil (5-FU) plus leucovorin.
Previous phase I studies showed increased gastrointestinal toxicity
(nausea) when UFT was administered in a single daily dose. Therefore,
a twice-daily schedule of administration was chosen for this study.
Weekly schedules of paclitaxel offer high dose intensity with limited
hematologic toxicity.[3-5] This combination has the advantage of ease
of administration and could be a well-tolerated outpatient regimen in
patients with metastatic solid tumor malignancies.
This phase I dose-escalation study will determine the maximum
tolerated dose of UFT on a twice-daily schedule that can be given
safely in combination with leucovorin along with weekly doses of
paclitaxel for 4 of 6 weeks. This study also will determine the
dose-limiting toxicities of UFT in this combination as well as define
the appropriate dose for phase II studies.
The study will enroll 9 to 24 men or women ³
18 years of age with metastatic solid tumor malignancies (excluding
colorectal cancer). Eligibility is based on several criteria.
Patients must have histologic proof of solid tumor malignancy
(excluding colorectal cancer) for which there is no reasonable
alternative therapy. They must also show radiographic or physical
examination documentation of metastatic disease, and not have had
major surgery within 2 weeks preceding the start of treatment.
Radiation therapy cannot occur within 2 weeks of beginning treatment.
Furthermore, patients must not have received chemotherapy within 4
weeks of beginning treatment.
In addition, patients must have a minimum life expectancy of 3 months
and an Eastern Cooperative Oncology Group performance status greater
than 2. There must be adequate bone marrow function, granulocytes ³
1.5 ´ 109/L, and platelets ³
1.0 ´ 1012/L. Bilirubin
must be £ 1.5 mg/dL and serum
creatinine £ 1.5 mg/dL. They must
also have no other serious medical or psychiatric illness and, for
premenopausal women, have negative pregnancy tests. All patients must
give informed consent.
Three patients will be enrolled in each cohort. Enrollment in the
next cohort will not occur until all patients in a cohort are fully
evaluable for toxicities (completed a 5-week cycle).
Dosing and Toxicity
The starting dose of oral UFT, 400 mg/day, is divided into two doses,
then escalated in steps of 100 mg/day. Leucovorin is to be
administered at 30 mg/bid for 28 days in combination with weekly
paclitaxel in 1-hour infusions of 80 mg/m² for 4 weeks every 6
weeks. The dosing for each cohort is shown in Table
If dose-limiting toxicity is not reached in any of three patients,
the UFT dose will continue to escalate in 100 mg/day increments in
cohorts of three patients. If it is reached in one of three patients,
the cohort will be expanded to six patients. If no other
dose-limiting toxicity occurs, the escalation of dose will continue
in cohorts of three patients.
All patients will be evaluated for toxicity based on the National
Cancer Institute Common Toxicity Criteria grading system.
Dose-limiting toxicity is defined as any instance of 1) grade 3
nonhematologic toxicity (excluding alopecia or nausea/vomiting); 2)
grade 4 hematologic toxicity (granulocyte colony-stimulating factor
is not allowed); 3) febrile neutropenia; 4) failure to deliver one of
the treatment courses for > 2 weeks for any toxicity-related reason.
Maximum tolerated dose (MTD) is defined as the maximum dose level for
which no more than two instances of dose-limiting toxicity are
observed in a cohort of a minimum of three patients and a maximum of
six. The recommended phase II dose will be one dose level below the MTD.
Duration of Therapy
Patients will continue therapy as long as their disease is
responding, unless toxicity prohibits further therapy. Patients with
stable disease may continue to receive therapy for up to six cycles
beyond their maximum response; those with documented disease
progression will be removed from the study. All patients completing
one cycle of therapy will be evaluable for response based on standard
If treatment is delayed during weekly dosing due to myelosuppression,
at resumption of the next cycle paclitaxel will be decreased by 10
mg/m²/day and UFT will be decreased by 100 mg/day. Such
reductions can occur only twice in any patient. The leucovorin dose
will remain at 30 mg with each UFT dose.
If grade 3/4 nonhematologic toxicity occurs, the UFT plus leucovorin
dose will be held and resumed when symptoms have completely resolved.
The UFT dose will then be reduced by 100 mg/day; leucovorin will
remain the same. For grade 2 diarrhea, UFT plus leucovorin will be
withheld and resumed at full dose after resolution of symptoms. If
therapy is withheld due to toxicity, those days of treatment are
counted as treatment days.
The purpose of this phase I study is to determine the maximum daily
dose and the dose-limiting toxicity of UFT when given in combination
with leucovorin along with weekly doses of paclitaxel in patients
with advanced solid tumor malignancies. Patient accrual is
anticipated to be approximately one to two patients per month. The
study is institutional review board-approved.
1. Ota K, Taguchi T, Kimura K: Report on nationwide pooled data and
cohort investigation in UFT phase II study. Cancer Chemother
Pharmacol 22:333-338, 1998.
2. Pazdur R, Lassere Y, Rhodes V, et al: Phase II trial of uracil and
tegafur plus oral leucovorin: An effective oral regimen in the
treatment of metastatic colorectal carcinoma. J Clin Oncol
3. Greco FA, Thomas M, Hainsworth JD: One-hour paclitaxel infusions:
Review of safety and efficacy. Cancer J Sci Am 5:179-191, 1999.
4. Seidman AD, Hudis CA, Albanel J, et al: Dose-dense therapy with
weekly 1-hour pacli-taxel infusions in the treatment of metastatic
breast cancer. J Clin Oncol 16:3353-3361, 1998.
5. Akerley W, Glantz M, Choy H, et al: Phase I trial of weekly
paclitaxel in advanced lung cancer. J Clin Oncol 16:153-158, 1998.