Irinotecan(Drug information on irinotecan) (CPT-11 [Camptosar]) is a novel semisynthetic analog of camptothecin that has recently become commercially available and continues to undergo extensive clinical evaluations. The unique mechanism of action of this agent, topoisomerase I inhibition, combined with preclinical studies assessing its efficacy and toxicologic profile, suggested the possibility of schedule-dependent antitumor and toxicologic effects.
In order to gain further insight into the potential schedule-dependency of irinotecan, this article will review the initial phase I studies that were conducted (Table 1). For simplicity, the studies have been grouped according to country and then by administration schedule. Phase I schedules that were explored initially can be grouped into single-dose, intermittent, and prolonged-infusion regimens. Interestingly, the irinotecan schedule favored for subsequent efficacy trials differed among the regions: Whereas the single-dose infusion every 3 weeks was used in France, both the United States and Japan selected a weekly regimen.
The principal toxicities noted for all of the administration schedules were diarrhea and neutropenia (Table 2, Table 3, Table 4, and Table 5). In the single-dose study in France, the institution of an intensive loperamide(Drug information on loperamide) regimen resulted in fewer episodes of serious diarrhea requiring hospitalization, and this regimen has since become part of standard supportive care.
Although the pharmacologic behavior of irinotecan will not be reviewed in detail in this article, pharmacodynamic relationships varied among the different studies and schedules (Table 6). Preliminary antitumor activity was noted in colon cancer refractory to fluorouracil(Drug information on fluorouracil) (5-FU) and advanced non-small-cell lung cancer, as well as other tumors. An interesting phase I/II trial conducted in Japan in patients with refractory or relapsed leukemia or lymphoma revealed evidence of a schedule-dependent antitumor effect.
The results of the phase I trials of irinotecan reflect the unique properties of this agent and should be used in choosing the optimal schedule for future efficacy and combination studies.
One of the earliest schedules of irinotecan explored was a single intravenous (IV) dose administered every 3 to 4 weeks. In a small phase I study conducted in 17 patients in Japan, doses ranged from 25 to 350 mg/m² administered by a 30-minute IV infusion.
The principal dose-limiting toxicity (DLT) was leukopenia, which appeared at doses ³ 100 mg/m² and became dose-limiting at 350 mg/m². The leukopenia occurred at approximately 7 days, with a median time to recovery of 16 days after the nadir. In addition, diarrhea was reported. The recommended phase II dose of 200 mg/m² was based on concerns about the combination of leukopenia and diarrhea at doses ³ 250 mg/m².
A second phase I study of irinotecan, conducted in France, extensively explored a single-dose administration schedule. The initial dose-finding portion of this trial included 64 patients (median age, 51 years), most of whom (60/64, 94%) had received prior therapy. The doses studied ranged from 100 to 750 mg/m² administered by a 30-minute IV infusion every 3 weeks.
An acute cholinergic syndrome was reported, consisting predominantly of gastrointestinal cramps and diaphoresis at doses ³ 260 mg/m², as well as salivation, visual disturbances, and lacrimation at doses of 300 to 750 mg/m². This syndrome occurred during and for 1 hour after the drug infusion. Atropine(Drug information on atropine) (0.25 to 0.50 mg) administered subcutaneously ameliorated these symptoms in two patients.
Noncumulative diarrhea, which began approximately 6 days after the administration of irinotecan, became dose-limiting at 260 mg/m², and a regimen of intensive loperamide was instituted to allow for further dose escalation. The high-dose loperamide regimen, which is now standard, consisted of 2 mg orally at the first diarrheal episode, followed by 2 mg every 2 hours until the patient had been free of diarrhea for a 12-hour period. With the advent of this regimen, the incidence of grade 3 or 4 diarrhea, which had been 50% at 260 mg/m², remained < 20% until the 750-mg/m² dose level, at which point neutropenia became dose-limiting.
Severe (grade 3 or 4) nausea and vomiting were uncommon (9%) in this study. The only other common nonhematologic toxicity was asthenia, which was reported in > 50% of patients at doses ³ 600 mg/m².
Hematologic toxicity, consisting of neutropenia, was the DLT of this schedule. Neutropenia developed between days 6 and 9 of therapy, and white blood cell count recovered in approximately 5 days. The neutropenia exhibited both interpatient and intrapatient variability, was noncumulative and resulted in complications primarily in patients who were heavily pretreated or had bone metastases. Thrombocytopenia was rare, and only two patients experienced grade 4 events.
The dose recommended for subsequent phase II studies was 350 mg/m², although it was suggested that a dose of 500 mg/m² be explored further in a feasibility study using high-dose loperamide.
A total of 34 patients were assessable for response in this study. Two complete responses (cervical and head and neck cancers) and six partial responses (5-FU-refractory colon cancer) occurred, all in previously treated patients.
The pharmacologic profile of irinotecan and its active metabolite, SN-38, showed linear pharmacokinetics, long terminal half-lives (~14 hours) for both compounds, and a statistically significant correlation between the area under the curve (AUC) of irinotecan and that of SN-38 (r = 0.60; P < .001). Interestingly, irinotecan was detected in saliva, sweat, and pleural fluid. In addition, the appearance of plasma rebound concentrations of both irinotecan and SN-38 suggested enterohepatic recirculation.
Pharmacodynamic analysis revealed a relationship between the extent of neutropenia for both irinotecan and SN-38, whereas only diarrhea up to grade 2 correlated with the AUCs of irinotecan and SN-38. Of note, in the extension of this trial, performed to gain experience at the 500- and 600-mg/m² dose levels, it was determined that 600 mg/m2 was not tolerated, resulting in grade 3 or 4 diarrhea or neutropenia in 64% and 78% of patients, respectively. The 500-mg/m² dose was considered acceptable in minimally pretreated patients, resulting in grade 3 or 4 diarrhea or neutropenia in 24% and 41% of patients, respectively.
In a third single-dose study performed in the United States, 32 patients (median age, 49 years) were treated with 100 to 345 mg/m² of irinotecan administered as a 90-minute infusion. Of the 32 patients, 30 had received prior therapy, and 13 of these were considered heavily pretreated.
In contrast to the French and Japanese studies, the DLT in the US study consisted of a constellation of severe hematologic and nonhematologic events at doses ³ 290 mg/m². Gastrointestinal toxicity, consisting of nausea, vomiting, anorexia, abdominal cramps, or diarrhea, became particularly prominent at doses ³ 240 mg/m². The nausea and vomiting occurred and resolved primarily in the peritreatment period, whereas anorexia persisted for 2 to 3 weeks in some patients, resulting in significant weight loss and a decline in performance status.
Both early and late diarrhea occurred. The early form was associated with cholinergic symptoms of diaphoresis and flushing, whereas the late form occurred 2 to 7 days following treatment and was not associated with these symptoms. A premedication regimen was instituted at the 240-mg/m² dose level, consisting of diphenhydramine(Drug information on diphenhydramine) 50 mg IV and ondansetron(Drug information on ondansetron) (Zofran) 0.15 mg/kg IV, both administered prior to treatment and then every 4 hours for 2 doses. Despite this premedication, irinotecan doses above 240 mg/m² resulted in unacceptable gastrointestinal toxicity. An intensive loperamide regimen was not used.
Both neutropenia and thrombocytopenia were prominent hematologic toxicities, although they were rarely dose-limiting. The recommended dose for subsequent trials of this schedule was 240 mg/m².
Three objective responses (all partial responses) were noted in this trial, occurring in previously treated patients with colon, renal, and cervical cancer.
The pharmacologic profile of irinotecan revealed linear pharmacokinetic behavior over the dose range studied. The AUCs for the lactone forms of irinotecan and SN-38 comprised 44% and 51% of their respective total AUCs, whereas the mean AUC values for the total and lactone forms of irinotecan were 12- to 34-fold higher than the AUC values for the total and lactone forms of SN-38.
No pharmacodynamic relationship was established between the gastrointestinal symptoms and the AUC of either forms of irinotecan or SN-38. In contrast, the decrement in neutrophils correlated with the exposure to total SN-38, but not to total or lactone irinotecan.