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

Masi, Gianluca; Falcone, Alfredo; Paolo, Antonello Di; Allegrini, Giacomo; Danesi, Romano; Barbara, C.; Cupini, Samanta; Tacca, M. Del

doi:10.1158/1078-0432.ccr-1585-3

Cited by 22 publications

(13 citation statements)

References 21 publications

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“…However, the toxicity profile and efficacy observed with our regimen generally corresponded to those of the TEGAFIRI regimens. In recent studies of irinotecan given as a low-dose continuous infusion, markedly increased systemic exposure to SN-38 [11,12,13] and a marked increase in the levels of the antiangiogenic marker thrombospondin-1 [14] were found, and encouraging antitumor activities were observed in previously treated cancer patients. Continuous infusional administration seems to be a promising method of delivering irinotecan.…”

Section: Discussionmentioning

confidence: 99%

Phase I/II Study of Twenty-Four-Hour Infusion of Irinotecan in Combination with Oral UFT plus Leucovorin for Metastatic Colorectal Cancer

Sadahiro¹,

Suzuki²,

Maeda³

et al. 2009

Oncology

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Objective: Irinotecan has, in general, been administered as a 90-min infusion. However, several studies have demonstrated that continuous infusion seems to be a promising method of delivering irinotecan. This phase I/II trial was performed to evaluate the efficacy and safety of continuous infusion of irinotecan combined with UFT plus leucovorin (LV) for metastatic colorectal cancer. Methods: Escalating doses of irinotecan (90–110 mg/m²) were administered by 24-hour infusion on day 1. UFT 300 mg/m²/day and LV 75 mg/day were administered orally, in 3 divided daily doses, on days 3–7 and 10–14. The treatment cycles were repeated every 2 weeks. Results: In the phase I study, the maximum tolerated dose of irinotecan was 110 mg/m² and the recommended dose for the phase II study was determined to be 100 mg/m². Thirty-six patients, including 3 patients at the recommended dose in the phase I study, were evaluated in the phase II study. The common grade 3/4 toxicities were leucopenia, neutropenia, diarrhea and anorexia. The response rate was 63.9%, and the median progression-free and overall survival times were 8.3 and 24.6 months, respectively. Conclusion: A 24-hour infusion of irinotecan combined with UFT/LV is feasible and active for metastatic colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Phase I/II Study of Twenty-Four-Hour Infusion of Irinotecan in Combination with Oral UFT plus Leucovorin for Metastatic Colorectal Cancer

Sadahiro¹,

Suzuki²,

Maeda³

et al. 2009

Oncology

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“…With our treatment regimen, irinotecan is administered at a relatively low dose of 100 mg/m 2 by continuous infusion over 24 h every 2 weeks and UFT is administered at a relatively high daily dose of 400 mg/m 2 with a 5 days on/2 days off intermittent schedule. In the recent phase I studies of irinotecan given as a continuous infusion, it was suggested that lower peak concentrations of SN-38 could lead to more efficient hepatic glucuronidation and biliary excretion, hence reducing systemic toxicity [36][37][38] . Moreover, in these studies, the markedly increased systemic exposure to SN-38 was found and encouraging antitumor activities were observed in pretreated patients with solid tumors.…”

Section: Discussionmentioning

confidence: 99%

Phase I/II Study of 24-Hour Infusion of Irinotecan Combined with Oral UFT for Metastatic Colorectal Cancer

Sadahiro

Suzuki²,

Maeda³

et al. 2008

Chemotherapy

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Background: To evaluate the efficacy and safety of irinotecan combined with UFT for untreated and pretreated metastatic colorectal cancer. Methods: Escalating doses of irinotecan (80–110 mg/m²) were administered by 24-hour infusion on day 1. UFT was administered orally at 400 mg/m²/day on days 3–7 and 10–14. The treatment cycles were repeated every 2 weeks. Results: In the phase I study, the maximum tolerated dose of irinotecan was 110 mg/m² and the recommended dose for the phase II study was determined to be 100 mg/m². Thirty-five patients including 3 patients at the recommended dose in the phase I study were evaluated in the phase II study. The grade 3/4 toxicities observed were leukopenia, neutropenia, thrombocytopenia and anemia. No grade 3 or more severe nonhematological toxicities were noted. The response rate was 62.9% and the median overall survival 16.7 months. Conclusions: A 24-hour infusion of irinotecan combined with UFT is feasible and active for metastatic colorectal cancer.

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“…The PK analysis of irinotecan and its main metabolites SN-38 and SN-38 glucuronide (SN-38glu) was performed as previously described (Masi et al, 2004) with minor modifications. Blood samples (4 ml each) for drug assays were taken from an indwelling i.v.…”

Section: Pharmacokinetics Of Metronomic Irinotecan Sn-38 and Sn-38 Gmentioning

confidence: 99%

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

et al. 2008

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The pharmacokinetics (PK) and pharmacodynamics (PD) of metronomic irinotecan have not been studied in cancer patients. The aim of the study is to investigate the PK/PD profile of irinotecan/SN-38 administered by metronomic schedule. Twenty chemotherapyrefractory or chemotherapy-resistant patients with metastatic colorectal carcinoma were enrolled. Irinotecan was infused continuously as follows: irinotecan 1.4 mg m À2 day À1 (n ¼ 7), 2.8 mg m À2 day À1 (n ¼ 5) and 4.2 mg m À2 day À1 (n ¼ 8). Drug levels were examined by HPLC, whereas ELISAs and real-time RT-PCR were used, respectively, for the measurement of plasma levels and gene expression in peripheral blood mononuclear cells of vascular endothelial growth factor/thrombospondin-1. Pharmacokinetic analysis demonstrated that the steady-state levels (C ss ) of SN-38 were between 1 and 3.3 ng ml À1 . From a PD point of view, higher thrombospondin-1 (TSP-1) plasma levels (153.4±30.1 and 130.4±9.2% at day 49 vs pretreatment values at 1.4 and 2.8 mg m À2 day À1 dose levels, respectively) and increased gene expression in PBMC were found during the metronomic irinotecan infusion, especially at the lower doses. Four patients (20%) obtained a stable disease (median 3.9 months) despite progressing during previous standard irinotecan schedule. Toxicities 4grade 1 were not observed. Metronomic irinotecan administration is very well tolerated and induces an increase of gene expression and plasma concentration of TSP-1 at low plasma SN-38 concentrations.

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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

Cited by 22 publications

References 21 publications

Phase I/II Study of Twenty-Four-Hour Infusion of Irinotecan in Combination with Oral UFT plus Leucovorin for Metastatic Colorectal Cancer

Phase I/II Study of Twenty-Four-Hour Infusion of Irinotecan in Combination with Oral UFT plus Leucovorin for Metastatic Colorectal Cancer

Phase I/II Study of 24-Hour Infusion of Irinotecan Combined with Oral UFT for Metastatic Colorectal Cancer

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

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