A Phase I Study of Paclitaxel, UFT, and Leucovorin

ABSTRACT: This phase I study examines the dose escalation of UFT given in combination with fixed doses of oral leucovorin and weekly doses of paclitaxel in patients with metastatic solid tumor malignancies (excluding colorectal cancer). There are two main objectives for this study. The first is to determine both the maximum tolerated dose and the dose-limiting toxicities of UFT when administered with leucovorin in combination with weekly paclitaxel (1-hour infusions of 80 mg/m² for 4 weeks every 6 weeks). The second is to define the appropriate dose for phase II studies. Both UFT and leucovorin combinations, as well as paclitaxel, are known to be effective as single agents in heavily pretreated patients with a variety of solid tumor malignancies. UFT plus leucovorin provide activity comparable to that of intravenously administered 5-fluorouracil plus leucovorin, and weekly schedules of paclitaxel offer high dose intensity with limited hematologic toxicity. This combination is advantageous in its ease of administration and could be a tolerated outpatient regimen in patients with metastatic solid tumor malignancies. [ONCOLOGY 14(Suppl 9):76-78, 2000]

Introduction

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.

Objectives

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.

Study Design

Patient Eligibility

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 1.

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.

Results

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 response criteria.

Dose Modifications

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.

Conclusions

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.

References:

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 11:2296-2300, 1994.

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.