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

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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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/m 2/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.

Original languageEnglish (US)
Pages (from-to)421-426
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume56
Issue number4
DOIs
StatePublished - Oct 2005
Externally publishedYes

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irinotecan
Cyclosporine
Colorectal Neoplasms
Modulation
Toxicity
Pharmacokinetics
Diarrhea

Keywords

  • Colorectal cancer
  • Cyclosporine
  • Irinotecan
  • Pharmacokinetic modulation

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Modulation of irinotecan with cyclosporine : A phase II trial in advanced colorectal cancer. / Desai, Apurva A.; Kindler, Hedy L.; Taber, David; Agamah, Edem; Mani, Sridhar; Wade-Oliver, Kurombi; Ratain, Mark J.; Vokes, Everett E.

In: Cancer Chemotherapy and Pharmacology, Vol. 56, No. 4, 10.2005, p. 421-426.

Research output: Contribution to journalArticle

Desai, AA, Kindler, HL, Taber, D, Agamah, E, Mani, S, Wade-Oliver, K, Ratain, MJ & Vokes, EE 2005, 'Modulation of irinotecan with cyclosporine: A phase II trial in advanced colorectal cancer', Cancer Chemotherapy and Pharmacology, vol. 56, no. 4, pp. 421-426. https://doi.org/10.1007/s00280-005-1020-5
Desai, Apurva A. ; Kindler, Hedy L. ; Taber, David ; Agamah, Edem ; Mani, Sridhar ; Wade-Oliver, Kurombi ; Ratain, Mark J. ; Vokes, Everett E. / Modulation of irinotecan with cyclosporine : A phase II trial in advanced colorectal cancer. In: Cancer Chemotherapy and Pharmacology. 2005 ; Vol. 56, No. 4. pp. 421-426.
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T2 - A phase II trial in advanced colorectal cancer

AU - Desai, Apurva A.

AU - Kindler, Hedy L.

AU - Taber, David

AU - Agamah, Edem

AU - Mani, Sridhar

AU - Wade-Oliver, Kurombi

AU - Ratain, Mark J.

AU - Vokes, Everett E.

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N2 - 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/m 2/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.

AB - 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/m 2/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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KW - Cyclosporine

KW - Irinotecan

KW - Pharmacokinetic modulation

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