Phase I and Pharmacologic Study of Irinotecan Administered as a 96-Hour Infusion Weekly to Adult Cancer Patients

Abstract

The recommended phase II dose of irinotecan of 10 mg/m(2)/d for 4 days weekly for 2 of 3 weeks was extremely well tolerated. Further efficacy testing of this pharmacologic strategy of administering intermittent low doses of irinotecan is warranted.

Proteasomal Degradation of Topoisomerase I Is Preceded by c-Jun NH2-Terminal Kinase Activation, Fas Up-Regulation, and Poly(ADP-Ribose) Polymerase Cleavage in SN38-Mediated Cytotoxicity against Multiple Myeloma

“…In clinical trials for relapsed refractory non-Hodgkin's lymphoma, there was no response using 200 mg/m 2 irinotecan every 3 to 4 weeks, whereas 40 mg/m 2 daily for 5 days every 3 to 4 weeks produced 17% complete remission and 17% partial remission (46). In addition, 96-hour infusions of 10 mg/m 2 resulted in no grade 3 or 4 toxicity, whereas 90-minute infusions of 125 mg/m 2 and 350 mg/m 2 every 3 weeks resulted in significant toxicity (47)(48)(49)(50). These clinical trials suggest that prolonged exposure to low doses of irinotecan may be associated with a significantly higher therapeutic index than short exposure to higher concentrations.…”

A randomised phase II multicentre trial of irinotecan (CPT-11) using four different schedules in patients with metastatic colorectal cancer

“…We also found a significant difference between the metabolic ratio of SN-38 between arms A and B, and B and C. A low, but very significant inverse correlation between dose and metabolic ratio of SN-38 was observed for arms A, B and C. A possible explanation for this change in metabolic ratio is saturation of the carboxylesterase reaction. The carboxylesterase reaction converting irinotecan into SN-38 in humans is very inefficient and deacylation dependent (Rivory et al, 1996;Haaz et al, 1997;Takimoto et al, 2000). The saturability of this enzymatic reaction may be of relevance for prolonged infusion schedules of irinotecan.…”

A Phase I and Pharmacokinetic Study of Irinotecan Given as a 7-Day Continuous Infusion in Metastatic Colorectal Cancer Patients Pretreated with 5-Fluorouracil or Raltitrexed

“…The starting dose of irinotecan was 20 mg/m 2 /day given as a 7-day continuous infusion (140 mg/m 2 cumulative dose) repeated every 3 weeks. This dose represented 40% of the dose intensity achieved with the recommended dose of 350 mg/m 2 administered as a 30 -90 min infusion every 3 weeks and a similar dose intensity achievable with a 14 days continuous infusion (16). The dose was escalated of 5 mg/m 2 /day in subsequent groups of patients up to determine MTD.…”

“…infusion (96 h and 14 days) is feasible with diarrhea being the dose-limiting toxicity (DLT) and with promising antitumor activity, especially in colorectal cancer patients. Pharmacokinetic analysis showed a greater SN-38/ irinotecan area under the time-concentration curve (AUC) ratio (0.24 and 0.16, 96 h versus 14 days, respectively) compared with the values observed after a 30 -90 min infusion (approximately 0.03-0.09) suggesting a more extensive metabolism of irinotecan to SN-38 (16,17). This observation may confirm the hypothesis of rate-limiting conversion of irinotecan to SN-38 and may explain, at least in part, the low dose-intensities achievable with the continuous infusion schedules.…”