D. Abigerges et al., PHASE-I AND PHARMACOLOGICAL STUDIES OF THE CAMPTOTHECIN ANALOG IRINOTECAN ADMINISTERED EVERY 3 WEEKS IN CANCER-PATIENTS, Journal of clinical oncology, 13(1), 1995, pp. 210-221
Purpose: A phase I study was undertaken to determine the maximum-toler
ated dose (MTD), principal toxicities, and pharmacokinetics of the nov
el topoisomerase I inhibitor irinotecan (CPT-11). Patients and Methods
: Sixty-four patients meeting I standard phase I eligibility criteria
were included (24 women, 40 men; median age, 51 years; primary sites:
colon, head and neck, lung, pleura; 60 of 64 had been previously treat
ed). Pharmacokinetics was determined by high-performance liquid chroma
tography (HPLC). Results: One hundred ninety CPT-11 courses were admin
istered as a 30-minute intravenous (IV) infusion every 3 weeks (100 to
750 mg/m(2)). Grade 3 to 4 nonhematologic toxicities included diarrhe
a (16%; three hospitalizations), nausea and vomiting (9%), asthenia (1
4%), alopecia (53%), elevation of hepatic transaminases (8%), and one
case of skin toxicity. An acute cholinergic syndrome wets observed dur
ing CPT-11 administration. Diarrhea appeared dose-limiting at 350 mg/m
(2), but this was circumvented by using a high-dose loperamide protoco
l that allowed dose escalation, Dose-dependent, reversible, noncumulat
ive granulocytopenia was the dose-limiting toxicity (nadir, days 6 to
9; median recovery time, 5 days). Grade 3 to 4 anemia was observed in
9% of patients. One patient died during the study, 8 days after CPT-11
treatment. Two complete responses (cervix, 450 mg/m(2); head and neck
, 750 mg/m(2)) and six partial responses in fluorouracil (5-FU)-refrac
tory colon cancer were observed (260 to 600 mg/m(2)). pharmacokinetics
of CPT-11 and active metabolite SN-38 were performed in 60 patients (
94 courses). CPT-11 plasma disposition was bi- or triphasic, with a me
an terminal half-life of 14.2 +/- 0.9 hours (mean +/- SEM]. The mean v
olume of distribution (Vdss) was 157 +/- 8 L/m(2), and total-body clea
rance was 15 a 1 L/m(2)/h. The CPT-11 area under the plasma concentrat
ion versus rime curves [AUG) and SN-38 AUC increased linearly with dos
e. SN-38 plasma decoy had an apparent half-life of 13.8 +/- 1.4 hours.
Both CPT-11 and SN-38 AUCs correlated with nadir leukopenia and granu
locytopenia, with grade 2 diarrhea, and with nausea and vomiting. Conc
lusion: The MTD of CPT-11 administered as a 30-minute IV infusion ever
y 3 weeks is 600 mg/m(2), with granulocytopenia being dose-limiting At
350 mg/m(2), diarrhea appeared dose-limiting, but high-dose loperamid
e reduced this toxicity and allowed dose escalation. For safety reason
s, the recommended dose is presently 350 mg/m(2) every 3 weeks; more e
xperience must be gained to establish the feasibility of a higher dose
in large multicentric phase II studies. However, when careful monitor
ing of gastrointestinal toxicities is possible, a higher dose of 500 m
g/m(2) could be recommended in good-risk patients. The activity of thi
s agent in 5-FU-refractory colorectal carcinoma makes it unique and ma
ndates expedited phase II testing. (C) 1995 by American Society of Cli
nical Oncology.