UFT Plus Calcium Folinate/Irinotecan in Colorectal Cancer

UFT Plus Calcium Folinate/Irinotecan in Colorectal Cancer

ABSTRACT: This phase I trial combining UFT plus oral calcium folinate (Orzel) with irinotecan (CPT-11) (Camptosar) for the treatment of patients with advanced or metastatic colorectal cancer will open shortly. Eligible patients will have locally advanced or metastatic colorectal cancer, and they may have received adjuvant chemotherapy (provided it has been completed more than 6 months prior to study entry), but will have not received any chemotherapy for advanced or metastatic disease. The primary objectives of this study will be to determine the side-effect profile, dose-limiting toxicities, and the maximum tolerated dose of this combination. A recommended starting dose for future trials will be defined. Response rates will also be observed as a secondary objective. The first cohort of six patients will receive irinotecan 200 mg/m² by intravenous infusion over 90 minutes on day 1 (the schedule that is in general use in Europe). On days 1 to 14, patients will receive UFT 250 mg/m²/d and calcium folinate 90 mg/d, both divided into three equal doses. This will be followed by a 1-week rest period with treatment for the next cycle resumed on day 22. In subsequent cohorts of six patients, UFT and irinotecan will in turn be escalated provided toxicity is acceptable. The calcium folinate dose will remain fixed at 90 mg/d throughout. The maximum tolerated dose is defined as that at which dose-limiting toxicities occur in more than one third of patients. The cohort of patients treated at the dose below the maximum tolerated dose will be expanded to a total of 20 patients to fully define the pattern of toxicities and activity of the combination. [ONCOLOGY 7(Suppl 3):51-54, 1999]


The single most important agent for the
systemic management of colorectal cancer remains 5-fluorouracil
(5-FU), both as adjuvant treatment and in advanced disease. Over the
last 40 years, a wide range of 5-FU schedules have been used, and in
parts of the world, it is now generally accepted that 5-FU is most
effective when given over a prolonged period with modulation by
calcium folinate. In the United States, the preferred schedule is
prolonged 5-FU infusion plus calcium folinate (leucovorin). One of
the limitations of 5-FU is that oral administration is not feasible.
However, prolonged infusion has important practical implications,
such as the need for hospital admission or placement of a long-term
central venous catheter. In addition, 5-FU has significant toxicities
due to its lack of specificity. UFT(uracil plus tegafur in a 4:1
molar ratio) plus oral calcium folinate (Orzel) is a novel, oral
fluoropyrimidine compound developed with the aim of offering more
convenient and better-tolerated therapy.

Initial Phase I and II Trials

Uracil and the fluoropyrimidine tegafur are combined in a molar ratio
of 4:1. Tegafur is converted to 5-FU in vivo; uracil is a pyrimidine
that inhibits the enzyme dihydropyrimidine dehydrogenase, which
controls the rate-limiting step in the degradation of 5-FU to 2-fluoro-b-alanine.
Fujii et al[1] have shown that the combination of uracil with
tegafur increases the accumulation of 5-FU in tumors and enhances its
antitumor activity in xenograft models without increased toxicity.

Given as a single agent, UFT plus oral calcium folinate has been
evaluated in a wide range of clinical trials. Initial phase I and II
trials were carried out in Japan,[2] and in the United States, phase
I studies with UFT plus oral calcium folinate used single weekly,
5-day, and 28-day dosing schedules. These studies identified phase II
doses for each schedule. Phase I studies using different UFT dose
schedules in combination with a fixed dose of calcium folinate were
extended in phase II trials to combine fixed-dose UFT with high-dose
(150 mg) or low-dose (15 mg) calcium folinate. Again, the activity of
UFT plus oral calcium folinate was confirmed,[3] leading to two large
multicenter phase III trials comparing UFT plus oral calcium folinate
with conventional 5-FU–based treatment.


Irinotecan (CPT-11) (Camptosar) is a semisynthetic derivative of
camptothecin, a plant alkaloid derived from the tree Camptotheca acuminata.
Irinotecan is converted to the active metabolite SN38, which
inhibits the enzyme DNA topoisomerase I, leading to lethal,
single-strand DNA breaks.[4] In preclinical studies, irinotecan was
active against a range of tumor types,[5] including those expressing
P-glycoprotein.[6] Phase I clinical studies were carried out in
Europe and Japan. In European studies, the dose-limiting toxicities
were neutropenia and diarrhea.[7-9] Based on results from these
trials, a dose of 350 mg/m2 given as an intravenous infusion over 60
to 90 minutes every 3 weeks was selected for European phase II
trials. By contrast, studies in Japan and in the United States are
utilizing irinotecan doses of 125 mg/m² or 150 mg/m² given
weekly or biweekly. Irinotecan is commercially available as
second-line treatment for patients with metastatic colorectal
cancer,[10] and has been shown to be superior to best supportive care
or retreatment with 5-FU in this setting.

Irinotecan has been given in combination with 5-FU in phase I studies
carried out in Japan, the United States, and Europe. A range of doses
and schedules of both compounds has been evaluated. In a United
States study, the maximum tolerated dose for 5-FU was 500 mg/m²
and 120 mg/m² for irinotecan when given weekly.[11] This
suggests that, although there are overlapping toxicities with these
two agents, they can be administered together, with irinotecan given
at the full single-agent dose. Although preliminary studies in Japan
raised the possibility of a pharmacokinetic interaction between 5-FU
and irinotecan,[12] this has not been confirmed in subsequent trials.[13]

Rationale for Current Study

5-Fluorouracil remains the single most widely used agent for the
treatment of advanced colorectal cancer. Irinotecan was the first
agent shown to be active in 5-FU–resistant disease. Since
irinotecan and 5-FU have different mechanisms of action and appear to
be “non–cross-resistant” in the clinic, it is
important to look at combinations of irinotecan and
fluoropyrimidines. A combination of the 5-FU prodrug UFT plus oral
calcium folinate has activity similar to that of 5-FU in advanced
colorectal cancer, but potential benefits in terms of its mode of
administration and toxicity profile. The combination of irinotecan
and UFT plus oral calcium folinate offers the prospect of a highly
active regimen that is convenient for the patient and easily
administered. It is likely that combination therapy will be of most
value as first-line treatment for advanced colorectal cancer, and it
is for this group of patients that larger, randomized studies are
envisaged. The current dose-finding phase I study of UFT plus oral
calcium folinate and irinotecan has been restricted to this group of
patients in order that the study results are applicable to future trials.

The aims of the study are 1) to determine the maximum tolerated dose
of UFT plus oral calcium folinate and irinotecan and to identify a
dose of the combination for future trials, and 2) to determine the
side-effect profile and the response rate of patients with advanced
metastatic or colorectal cancer treated with UFT plus oral calcium
folinate and irinotecan.

Trial Design

This is a nonrandomized, open-label, two-center phase I trial
designed primarily to determine the safety and maximum tolerated dose
of UFT plus oral calcium folinate and irinotecan given in escalating
doses with a fixed dose of calcium folinate. Initially, six patients
will be treated with irinotecan 200 mg/m² given as a 90-minute
IV infusion on day 1, and UFT 250 mg/m²/d with calcium folinate
90 mg/d, both given orally in three divided doses over 14 days. This
will be followed by a 1-week rest period; treatment will recommence
if the patient does not experience dose-limiting toxicities or
progressive disease, and wants to continue treatment (Figure
). Dose escalation will continue in subsequent cohorts as shown
in Table 1. In brief, with the
calcium folinate dose fixed at 90 mg/d, the dose of irinotecan will
be increased from 200 to 250 mg/m², then to 300 mg/m². If
this is tolerated, the dose of UFT will be escalated from 250 to 300
mg/m²/d, then to 350 mg/m²/d. The maximum tolerated dose
will be the dose at which more than two of six patients experience
dose-limiting toxicities during the first cycle of treatment.
Dose-limiting toxicities include grade 3 or 4 neutropenia complicated
by fever, requiring IV antibiotics, associated with grade 3 or 4
diarrhea, or persisting for more than 7 days. Grade 4
thrombocytopenia and grade 3 or 4 nonhematologic toxicities, with the
exception of alopecia or nausea and vomiting, will also be dose-limiting.

Disease sites will be assessed at baseline and after every three
cycles of treatment while on study and at the end of treatment. In
most cases, assessment will be by computed tomography scan with
additional imaging performed where clinically indicated.


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