UFT/Leucovorin Plus Weekly Irinotecan in Advanced or Metastatic Colorectal Cancer

ABSTRACT: This is an open-label, nonrandomized phase I trial to determine the safety and maximum tolerated dose of irinotecan with a fixed dose of UFT plus oral leucovorin in patients with advanced or metastatic colorectal cancer. A secondary objective of the study is to determine the response rate in this patient population. Adult patients with histologically confirmed advanced or metastatic colorectal carcinoma and no prior chemotherapy for advanced or metastatic disease, or those patients who have received adjuvant chemotherapy (> 6 months prior to the study entry) will be eligible to participate. All patients must have measurable or evaluable lesions. Symptoms will be evaluated at baseline and every 6 weeks thereafter. Computed tomography scans will be performed at baseline and every three cycles of treatment to assess tumor response. A total of six cycles of treatment may be given, depending on patient tolerance. Patients will be followed for a maximum of 12 months for time to progression, following the last dose of the study drug. Tumor response will be defined using standard World Health Organization criteria. [ONCOLOGY 14(Suppl 9):37-40, 2000]

Introduction

The combination of irinotecan (Camptosar, CPT-11), a topoisomerase I inhibitor, with fluorouracil (5-FU) has been used successfully to treat advanced colorectal cancer. In large clinical trials there were significant advantages for this combination compared with 5-FU/leucovorin alone. The main toxicities and dose-limiting toxicities (DLTs) of this combination were diarrhea, nausea, and neutropenia.

UFT (uracil and tegafur) has shown efficacy in advanced colorectal cancer both as a single agent[1,2] and in combination with oral leucovorin (a combination being developed under the trade name Orzel).[3-5] UFT possesses significant benefits over 5-FU in terms of its route of administration, toxicity profile, and pharmacokinetics. Furthermore, UFT is well tolerated, is less myelosuppressive than 5-FU (< 5% for UFT compared with up to 20% for 5-FU), and results in a lower incidence of nausea and vomiting.[6-10]

Because of the oral administration of UFT plus leucovorin, there may be additional advantages for its combination with irinotecan.

The primary objectives of the study are the determination of the maximum tolerated dose (MTD) of the combination of irinotecan with a fixed dose of UFT plus oral leucovorin; establishment of the starting dose for the phase II study; determination of the side-effect profile; and assessment of the DLT of the combination of irinotecan and UFT plus leucovorin. Secondary objectives are the determination of the response rate in patients with advanced or metastatic colorectal cancer and the pharmacokinetics of irinotecan.

Study Design

This phase I, open-label, dose-escalation trial is designed to determine the safety, DLTs, and MTD of irinotecan with a fixed dose of UFT plus leuco-vorin in patients with advanced or metastatic colorectal cancer.

One cycle of treatment will be of a 6-week duration. A maximum of six cycles of treatment will be administered per cohort, as shown in Table 1.

Initially, three of six patients will be treated weekly for 4 weeks. The combined regimen will be followed by a 2-week rest period, thus ending the cycle. At the end of the first cycle, providing DLT occurs in one or fewer of three patients, the remaining three patients of the first cohort will be treated with the same dose schedule. If two or fewer of six patients in this cohort experience a DLT, the dose level of irinotecan will be escalated for the next cohort of three to six patients; otherwise dose escalation stops. If no DLTs are observed in the first three patients of the cohort, this cohort level will close and the next three patients will begin treatment in the second cohort. This will be the case in all cohorts if no DLTs are observed in the first three patients (Figure 1).

The patients in each cohort will continue to receive the assigned dose schedule until disease progression is determined or unacceptable toxicity occurs, for a maximum of six cycles. Cohorts of three to six patients will be treated at each dose level until the MTD is reached. The MTD of irinotecan in combination with UFT plus leucovorin is defined as that dose level at which DLTs occur in more than two of six patients. Having established the MTD, the cohort below the MTD (starting dose for phase II) will be expanded to include 20 patients to more fully characterize the toxicity profile.

Inclusion Criteria

Inclusion criteria are as follows: (1) histologically confirmed advanced or metastatic colorectal carcinoma; (2) adjuvant chemotherapy (> 6 months prior to study entry); (3) no prior chemotherapy, but disease for which treatment with fluoropyrimidine or topoisomerase I inhibitors may be appropriate; (4) measurable or evaluable disease; (5) male or female (with negative pregnancy test); (6) age ³ 18 years; (7) Eastern Cooperative Oncology Group performance status 0 to 2; (8) adequate serum chemistry; (9) adequate bone marrow function; (10) possible follow-up of the patient; and (11) patient’s consent according to local Ethics Committee requirements.

Exclusion Criteria

Exclusion criteria are as follows (1) prior radiotherapy except palliative radiotherapy for control of symptomatic disease; (2) life-threatening toxicities as a result of fluoropyrimidine treatment; (3) medical or psychiatric contradiction; (4) known brain metastases; (5) ulcerative colitis or Crohn’s disease; (6) pregnant or breast-feeding women, or women not using adequate methods of birth control; (7) any condition or therapy that may pose a risk to the patient or interfere with study objectives; and (8) any other investigational drug given within 30 days of initiation of therapy, and participation in other clinical studies.

Conclusions

Two patients have been enrolled in the first treatment level to date. Study recruitment is ongoing. The first results will be expected in a few months.

References:

1. Malik STA, Talbot D, Clark PI, et al: Phase II trial of UFT in advanced colorectal and gastric cancer. Br J Cancer 62:1023-1025, 1990.

2. Ota K, Taguchi T, Kimura K, et al: Report on nationwide pooled data and cohort investigation in UFT phase II study. Cancer Chemother Pharmacol 22:333-338, 1980.

3. Saltz LB, Leichman CG, Young CW, et al: A fixed-ratio combination of uracil and ftorafur (UFT) with low-dose leucovorin. An active oral regimen for advanced colorectal cancer. Cancer 75:782-785, 1995.

4. Gonzales-Baron M, Feliu J, de la Gandara I, et al: Efficacy of oral tegafur modulation by uracil and leucovorin in advanced colorectal cancer. A phase II study. Eur J Cancer 31A:2215-2219, 1995.

5. 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 12:2269-2300, 1994.

6. Pazdur R, Douillard JY, Skillings JR, et al: Multicenter phase III study of 5-fluorouracil (5-FU) or UFT in combination with leucovorin (LV) in patients with metastatic colorectal cancer (abstract 1009). Proc Am Soc Clin Oncol 18:263a, 1999.

7. Carmichael J, Popiela T, Radstone D, et al: Randomized comparative study of ORZEL (oral uracil/tegafur {UFT] plus leucovorin [LV] versus parenteral 5-fluorouracil (5-FU) plus LV in patients with metastatic colorectal cancer (abstract 1015). Proc Am Soc Clin Oncol 18:264a, 1999.

8. Meropol NJ, Rustum YM, Petrelli NJ, et al: A phase I and pharmacokinetic study of oral uracil, ftorafur, and leucovorin in patients with advanced cancer. Cancer Chemother Pharmacol 37:581-586, 1996.

9. Diasio RB: Improving fluorouracil chemotherapy with novel orally administered fluoropyrimidines. Drugs 58:(suppl 3):119-126, 1999.

10. Macdonald JS: Oral fluoropyrimidines: A closer look at their toxicities. Am J Clin Oncol 22:475-480, 1999.