The combination of irinotecan (CPT-11, Camptosar) and fluorouracil
(5-FU) has proven to be an effective agent against advanced
malignancies. Furthermore, maximal activity occurs when irinotecan is
administered prior to 5-FU.[1,2] Recent randomized trials have shown
the combination to produce improved response rates, progression-free
survival, and overall survival when compared to 5-FU alone in
patients with metastatic colorectal cancer.[3,4]
This phase I trial is an evaluation of sequential, ascending doses of
irinotecan combined with UFT (uracil and tegafur) plus oral
leucovorin (a combination being developed under the trade name Orzel)
in a fixed dose when administered to patients with advanced malignancies.
This trial is designed to (1) determine the maximum tolerated doses
of combined irinotecan and UFT plus leucovorin at 60 mg/d when
administered to patients with cancer; (2) describe the toxicities
observed with the combination; (3) describe the pharmacokinetics of
each drug when administered in this combination; and 4) obtain
preliminary evidence of antitumor activity.
Patients with histologically confirmed solid tumors, measurable or
evaluable disease, and no effective treatment options are eligible.
Other requirements are Eastern Cooperative Oncology Group performance
status of 0 to 2 and no chemotherapy/radiotherapy for 3 weeks prior
to study entry. Baseline laboratory values are absolute granulocyte
count ³ 1,500 ´ 109/L;
platelet count ³ 100,000 ´ 109/L;
serum creatinine £ 2.0 mg/dL; total
bilirubin £ 1.5 mg/dL; aspartate aminotransferase/alanine
aminotransferase £ 2.5 ´
upper limit of normal. Patient characteristics are shown in Table
Treatment consists of escalating doses of irinotecan as a 90-minute
intravenous infusion on day 1, followed by oral UFT twice daily on
days 2 through 15, and a fixed dose of oral leucovorin twice daily on
days 2 through 15. Starting doses were irinotecan 200 mg/m²/d,
UFT 200 mg/m²/d, and leucovorin 60 mg/d. Cycles are repeated
every 21 days (Table 2).
Dose-limiting toxicity is defined as grade 4 neutropenia lasting >
5 days, grade 3/4 neutropenia with fever > 101°F, platelet
count < 25,000 ´ 109/L,
and grade 3/4 nonhematologic toxicity. Maximum tolerated dose is
defined as one dose level below the doses that produced dose-limiting
toxicity in more than one third of patients. A total of 10 to 12
patients will be treated at the maximum tolerated dose to better
define these as the recommended doses for phase II evaluation.
One patient with non-small-cell lung cancer (NSCLC) treated at the
initial dose level experienced dose-limiting toxicity in the form of
grade 4 diarrhea, nausea/vomiting, and mucositis, prompting expansion
of that level to six patients. Of the patients evaluable for
antitumor response, the patient noted above maintained stable disease
following two cycles of therapy and continues on treatment.
Irinotecan, SN-38, and 5-FU pharmacokinetic analyses will be
performed on all patients. (Irinotecan is a soluble prodrug that is
converted in vivo to the highly active SN-38.) Accrual continues at
the initial dose level. (Toxicity results are outlined in Table
Only three patients are evaluable for response to date. One patient
with NSCLC chose to discontinue treatment after one cycle, and one
patient has yet to complete cycle 2. One patient has stable disease
and two have experienced disease progression.
Another patient with NSCLCand who received prior docetaxel
(Taxotere), vinorelbine (Navelbine), and gemcitabine
(Gemzar)maintained disease stabilization at her metastatic
sites after two cycles and continues on therapy. Two patients with
colon cancer experienced disease progression after one and two
treatment cycles, respectively.
Preliminary results indicate that the combination of irinotecan and
UFT plus leucovorin is well tolerated at these initial doses,
although dose-limiting toxicity was observed in one patient.
Antitumor activity was observed in one patient with NSCLC. Accrual
continues at the initial dose level (expanded to six patients), and
pharmacokinetic analyses are ongoing.
1. Guichard S, Caliaro MJ, Houin G, et al: Sequential exposure to
irinotecan and 5-fluorouracil is synergistic in human colon carcinoma
HT29 cell line (abstract). Proc Am Assoc Cancer Res 37:292, 1996.
2. Mans DRA, Brondani da Rocha A, Vargas Schwartzbold C, et al:
Assessment of the efficacy of the irinotecan/5-fluorouracil
combination in a panel of human colon carcinoma cell lines
(abstract). Proc Am Assoc Cancer Res 37:291, 1996.
3. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil
and leucovorin for metastatic colorectal cancer. N Engl J Med
4. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined
with fluorouracil compared with fluorouracil alone as first-line
treatment for metastatic colorectal cancer: A multicenter randomized
trial. Lancet 355:1041-1047, 2000.