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Modulation of irinotecan with cyclosporine: a phase II trial in advanced colorectal cancer

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Abstract

Introduction: Despite the extensive clinical experience with irinotecan, significant concerns remain regarding its toxicity. In a phase I trial, we modulated irinotecan pharmacokinetics by inhibiting biliary excretion of SN-38, the active metabolite of irinotecan, using cyclosporine. The modulation appeared to decrease the gastrointestinal toxicity of irinotecan and suggested that irinotecan activity might also be retained. Hence, we conducted this phase II trial in patients with colorectal cancer (CRC) to further evaluate the toxicity and activity of irinotecan modulated with cyclosporine. Patients and Methods: Sixteen patients with 5-fluorouracil refractory CRC were treated. Cyclosporine (5 mg/kg) was administered as a 6-h infusion and irinotecan (60 mg/m2/day, 90-min infusion) was started 3 h after initiation of the Cyclosporine. Both agents were given weekly for 4 weeks, every 6 weeks. Responses were assessed every 12 weeks, and toxicity was monitored weekly. Results: Sixteen patients were evaluable for toxicity and 11 for response. There was 1 partial response (6%). Five patients had SD lasting a median of 12 weeks. Grade 3/4 diarrhea was observed in only 13% of the patients. Conclusion: Pharmacokinetic modulation of irinotecan using parenteral cyclosporine appears to decrease the incidence of diarrhea in CRC patients. Given the modest activity of irinotecan monotherapy, a larger study would be required to assess if the modulation improves the toxicity without compromising this activity. The available clinical data suggest that pharmacokinetic modulation of irinotecan should be evaluated further to define its optimal clinical utility.

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Acknowledgements

The authors most importantly acknowledge the patients and their families for their participation and support of this research. The authors also greatfully acknowledge all other physicians, nurses and data managers involved in the conduct of the study. This trial was supported in part by grants U01CA63187-01 and P30 CA14599.

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Authors and Affiliations

  1. Section of Hematology/Oncology, University of Chicago, 5841 S. Maryland Avenue, MC 2115, Chicago, IL, 60637, USA

    Apurva A. Desai, Hedy L. Kindler, Sridhar Mani, Kurombi Wade-Oliver, Mark J. Ratain & Everett E. Vokes

  2. Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, USA

    Apurva A. Desai & Mark J. Ratain

  3. University of Chicago Cancer Research Center, USA

    Hedy L. Kindler, Sridhar Mani, Mark J. Ratain & Everett E. Vokes

  4. Michiana Hematology/Oncology, 922 E Colfax, South Bend, IN, 46617, USA

    David Taber

  5. Central Illinois Hematology/Oncology Center, Springfield, IL, USA

    Edem Agamah

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  1. Apurva A. Desai
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  2. Hedy L. Kindler
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  3. David Taber
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  7. Mark J. Ratain
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  8. Everett E. Vokes
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Correspondence to Apurva A. Desai.

Additional information

Two of the co-authors: Edem Agamah (owns shares of Pfizer) and Mark J. Ratain [Co-inventor on several patents (pending/issued) related to the modulation or irinotecan and/or its Pharmacogenetics] would like to declare their potential conflicts of interest.

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Desai, A.A., Kindler, H.L., Taber, D. et al. Modulation of irinotecan with cyclosporine: a phase II trial in advanced colorectal cancer. Cancer Chemother Pharmacol 56, 421–426 (2005). https://doi.org/10.1007/s00280-005-1020-5

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  • DOI: https://doi.org/10.1007/s00280-005-1020-5

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