A randomised phase III trial of the pharmacokinetic biomodulation of irinotecan using oral ciclosporin in advanced colorectal cancer: results of the Panitumumab, Irinotecan & Ciclosporin in COLOrectal cancer therapy trial (PICCOLO)

Gary Middleton; Sarah Brown; Catherine Lowe; Timothy Maughan; Stephen Gwyther; Alfred Oliver; Susan Richman; Denise Blake; Vicky Napp; Helen Marshall; Jonathan Wadsley; Nick Maisey; Ian Chau; Mark Hill; Simon Gollins; Sun Myint; Sarah Slater; John Wagstaff; John Bridgewater; Matthew Seymour

doi:10.1016/j.ejca.2013.06.017

A randomised phase III trial of the pharmacokinetic biomodulation of irinotecan using oral ciclosporin in advanced colorectal cancer: results of the Panitumumab, Irinotecan & Ciclosporin in COLOrectal cancer therapy trial (PICCOLO)

Gary Middleton, Sarah Brown, Catherine Lowe, Timothy Maughan, Stephen Gwyther, Alfred Oliver, Susan Richman, Denise Blake, Vicky Napp, Helen Marshall, Jonathan Wadsley, Nick Maisey, Ian Chau, Mark Hill, Simon Gollins, Sun Myint, Sarah Slater, John Wagstaff, John Bridgewater, Matthew Seymour

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

17 Citations (Scopus)

Abstract

BACKGROUND: The main toxicity of irinotecan in advanced colorectal cancer (CRC) is delayed diarrhoea. Intestinal SN-38, released by deconjugation of the parent glucuronide excreted into the bile or produced in situ by intestinal carboxylesterase, is toxic to the intestinal epithelium. The canalicular transport of irinotecan and SN-38G is mediated by ABCC2 (MRP2) and ABCB1 (MDR1) which are both inhibited by ciclosporin. We tested whether irinotecan and ciclosporin was non-inferior for anti-cancer efficacy and superior for toxicity compared with single-agent irinotecan.

METHODS: Six hundred and seventy-two patients with advanced, measurable CRC following prior fluoropyrimidine-containing chemotherapy were randomised to either irinotecan 3-weekly 350 mg/m(2) (or 300 mg/m(2) if age >70 or performance status (PS)=2) or 3-weekly irinotecan at 140 mg/m(2) (120 mg/m(2) if age >70 or PS=2) with ciclosporin 3mg/kg t.d.s. for three days by mouth starting on the morning before irinotecan. The primary end-point was the proportion of patients alive and progression-free at 12 weeks. The key secondary end-point was the incidence of grade ≥3 diarrhoea within 12 weeks of randomisation.

RESULTS: The proportion of patients progression-free at 12 weeks with irinotecan was 53.4% compared to 47.2% with irinotecan plus ciclosporin (difference=-6.3%, 95% confidence interval (CI) [-13.8%, 1.3%]). Since the lower limit of the 95% CI crossed the pre-specified non-inferiority margin of -10.6%, non-inferiority of irinotecan plus ciclosporin compared to irinotecan alone was not statistically demonstrated. 15.0% patients developed severe diarrhoea on irinotecan compared to 13.8% on irinotecan plus ciclosporin, a non-significant difference.

INTERPRETATION: The pharmacokinetic biomodulation of irinotecan using oral ciclosporin does not improve the therapeutic index of irinotecan in advanced CRC.

FUNDING: The trial was funded by Cancer Research UK and supported by Amgen Pharma.

Original language	English
Pages (from-to)	3507-16
Number of pages	10
Journal	European Journal of Cancer
Volume	49
Issue number	16
DOIs	https://doi.org/10.1016/j.ejca.2013.06.017
Publication status	Published - Nov 2013

Bibliographical note

Keywords

Administration, Oral
Aged
Antibodies, Monoclonal
Antineoplastic Combined Chemotherapy Protocols
Biological Availability
Camptothecin
Colorectal Neoplasms
Cyclosporine
Diarrhea
Disease-Free Survival
Drug Administration Schedule
Female
Great Britain
Humans
Kaplan-Meier Estimate
Male
Middle Aged
Multidrug Resistance-Associated Proteins
Odds Ratio
P-Glycoprotein
Time Factors
Treatment Outcome

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Middleton, G., Brown, S., Lowe, C., Maughan, T., Gwyther, S., Oliver, A., Richman, S., Blake, D., Napp, V., Marshall, H., Wadsley, J., Maisey, N., Chau, I., Hill, M., Gollins, S., Myint, S., Slater, S., Wagstaff, J., Bridgewater, J., & Seymour, M. (2013). A randomised phase III trial of the pharmacokinetic biomodulation of irinotecan using oral ciclosporin in advanced colorectal cancer: results of the Panitumumab, Irinotecan & Ciclosporin in COLOrectal cancer therapy trial (PICCOLO). European Journal of Cancer, 49(16), 3507-16. https://doi.org/10.1016/j.ejca.2013.06.017

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abstract = "BACKGROUND: The main toxicity of irinotecan in advanced colorectal cancer (CRC) is delayed diarrhoea. Intestinal SN-38, released by deconjugation of the parent glucuronide excreted into the bile or produced in situ by intestinal carboxylesterase, is toxic to the intestinal epithelium. The canalicular transport of irinotecan and SN-38G is mediated by ABCC2 (MRP2) and ABCB1 (MDR1) which are both inhibited by ciclosporin. We tested whether irinotecan and ciclosporin was non-inferior for anti-cancer efficacy and superior for toxicity compared with single-agent irinotecan.METHODS: Six hundred and seventy-two patients with advanced, measurable CRC following prior fluoropyrimidine-containing chemotherapy were randomised to either irinotecan 3-weekly 350 mg/m(2) (or 300 mg/m(2) if age >70 or performance status (PS)=2) or 3-weekly irinotecan at 140 mg/m(2) (120 mg/m(2) if age >70 or PS=2) with ciclosporin 3mg/kg t.d.s. for three days by mouth starting on the morning before irinotecan. The primary end-point was the proportion of patients alive and progression-free at 12 weeks. The key secondary end-point was the incidence of grade ≥3 diarrhoea within 12 weeks of randomisation.RESULTS: The proportion of patients progression-free at 12 weeks with irinotecan was 53.4% compared to 47.2% with irinotecan plus ciclosporin (difference=-6.3%, 95% confidence interval (CI) [-13.8%, 1.3%]). Since the lower limit of the 95% CI crossed the pre-specified non-inferiority margin of -10.6%, non-inferiority of irinotecan plus ciclosporin compared to irinotecan alone was not statistically demonstrated. 15.0% patients developed severe diarrhoea on irinotecan compared to 13.8% on irinotecan plus ciclosporin, a non-significant difference.INTERPRETATION: The pharmacokinetic biomodulation of irinotecan using oral ciclosporin does not improve the therapeutic index of irinotecan in advanced CRC.FUNDING: The trial was funded by Cancer Research UK and supported by Amgen Pharma.",

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author = "Gary Middleton and Sarah Brown and Catherine Lowe and Timothy Maughan and Stephen Gwyther and Alfred Oliver and Susan Richman and Denise Blake and Vicky Napp and Helen Marshall and Jonathan Wadsley and Nick Maisey and Ian Chau and Mark Hill and Simon Gollins and Sun Myint and Sarah Slater and John Wagstaff and John Bridgewater and Matthew Seymour",

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Middleton, G, Brown, S, Lowe, C, Maughan, T, Gwyther, S, Oliver, A, Richman, S, Blake, D, Napp, V, Marshall, H, Wadsley, J, Maisey, N, Chau, I, Hill, M, Gollins, S, Myint, S, Slater, S, Wagstaff, J, Bridgewater, J & Seymour, M 2013, 'A randomised phase III trial of the pharmacokinetic biomodulation of irinotecan using oral ciclosporin in advanced colorectal cancer: results of the Panitumumab, Irinotecan & Ciclosporin in COLOrectal cancer therapy trial (PICCOLO)', European Journal of Cancer, vol. 49, no. 16, pp. 3507-16. https://doi.org/10.1016/j.ejca.2013.06.017

A randomised phase III trial of the pharmacokinetic biomodulation of irinotecan using oral ciclosporin in advanced colorectal cancer: results of the Panitumumab, Irinotecan & Ciclosporin in COLOrectal cancer therapy trial (PICCOLO). / Middleton, Gary; Brown, Sarah; Lowe, Catherine et al.
In: European Journal of Cancer, Vol. 49, No. 16, 11.2013, p. 3507-16.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - A randomised phase III trial of the pharmacokinetic biomodulation of irinotecan using oral ciclosporin in advanced colorectal cancer

T2 - results of the Panitumumab, Irinotecan & Ciclosporin in COLOrectal cancer therapy trial (PICCOLO)

AU - Middleton, Gary

AU - Brown, Sarah

AU - Lowe, Catherine

AU - Maughan, Timothy

AU - Gwyther, Stephen

AU - Oliver, Alfred

AU - Richman, Susan

AU - Blake, Denise

AU - Napp, Vicky

AU - Marshall, Helen

AU - Wadsley, Jonathan

AU - Maisey, Nick

AU - Chau, Ian

AU - Hill, Mark

AU - Gollins, Simon

AU - Myint, Sun

AU - Slater, Sarah

AU - Wagstaff, John

AU - Bridgewater, John

AU - Seymour, Matthew

PY - 2013/11

Y1 - 2013/11

N2 - BACKGROUND: The main toxicity of irinotecan in advanced colorectal cancer (CRC) is delayed diarrhoea. Intestinal SN-38, released by deconjugation of the parent glucuronide excreted into the bile or produced in situ by intestinal carboxylesterase, is toxic to the intestinal epithelium. The canalicular transport of irinotecan and SN-38G is mediated by ABCC2 (MRP2) and ABCB1 (MDR1) which are both inhibited by ciclosporin. We tested whether irinotecan and ciclosporin was non-inferior for anti-cancer efficacy and superior for toxicity compared with single-agent irinotecan.METHODS: Six hundred and seventy-two patients with advanced, measurable CRC following prior fluoropyrimidine-containing chemotherapy were randomised to either irinotecan 3-weekly 350 mg/m(2) (or 300 mg/m(2) if age >70 or performance status (PS)=2) or 3-weekly irinotecan at 140 mg/m(2) (120 mg/m(2) if age >70 or PS=2) with ciclosporin 3mg/kg t.d.s. for three days by mouth starting on the morning before irinotecan. The primary end-point was the proportion of patients alive and progression-free at 12 weeks. The key secondary end-point was the incidence of grade ≥3 diarrhoea within 12 weeks of randomisation.RESULTS: The proportion of patients progression-free at 12 weeks with irinotecan was 53.4% compared to 47.2% with irinotecan plus ciclosporin (difference=-6.3%, 95% confidence interval (CI) [-13.8%, 1.3%]). Since the lower limit of the 95% CI crossed the pre-specified non-inferiority margin of -10.6%, non-inferiority of irinotecan plus ciclosporin compared to irinotecan alone was not statistically demonstrated. 15.0% patients developed severe diarrhoea on irinotecan compared to 13.8% on irinotecan plus ciclosporin, a non-significant difference.INTERPRETATION: The pharmacokinetic biomodulation of irinotecan using oral ciclosporin does not improve the therapeutic index of irinotecan in advanced CRC.FUNDING: The trial was funded by Cancer Research UK and supported by Amgen Pharma.

AB - BACKGROUND: The main toxicity of irinotecan in advanced colorectal cancer (CRC) is delayed diarrhoea. Intestinal SN-38, released by deconjugation of the parent glucuronide excreted into the bile or produced in situ by intestinal carboxylesterase, is toxic to the intestinal epithelium. The canalicular transport of irinotecan and SN-38G is mediated by ABCC2 (MRP2) and ABCB1 (MDR1) which are both inhibited by ciclosporin. We tested whether irinotecan and ciclosporin was non-inferior for anti-cancer efficacy and superior for toxicity compared with single-agent irinotecan.METHODS: Six hundred and seventy-two patients with advanced, measurable CRC following prior fluoropyrimidine-containing chemotherapy were randomised to either irinotecan 3-weekly 350 mg/m(2) (or 300 mg/m(2) if age >70 or performance status (PS)=2) or 3-weekly irinotecan at 140 mg/m(2) (120 mg/m(2) if age >70 or PS=2) with ciclosporin 3mg/kg t.d.s. for three days by mouth starting on the morning before irinotecan. The primary end-point was the proportion of patients alive and progression-free at 12 weeks. The key secondary end-point was the incidence of grade ≥3 diarrhoea within 12 weeks of randomisation.RESULTS: The proportion of patients progression-free at 12 weeks with irinotecan was 53.4% compared to 47.2% with irinotecan plus ciclosporin (difference=-6.3%, 95% confidence interval (CI) [-13.8%, 1.3%]). Since the lower limit of the 95% CI crossed the pre-specified non-inferiority margin of -10.6%, non-inferiority of irinotecan plus ciclosporin compared to irinotecan alone was not statistically demonstrated. 15.0% patients developed severe diarrhoea on irinotecan compared to 13.8% on irinotecan plus ciclosporin, a non-significant difference.INTERPRETATION: The pharmacokinetic biomodulation of irinotecan using oral ciclosporin does not improve the therapeutic index of irinotecan in advanced CRC.FUNDING: The trial was funded by Cancer Research UK and supported by Amgen Pharma.

KW - Administration, Oral

KW - Aged

KW - Antibodies, Monoclonal

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Biological Availability

KW - Camptothecin

KW - Colorectal Neoplasms

KW - Cyclosporine

KW - Diarrhea

KW - Disease-Free Survival

KW - Drug Administration Schedule

KW - Female

KW - Great Britain

KW - Humans

KW - Kaplan-Meier Estimate

KW - Male

KW - Middle Aged

KW - Multidrug Resistance-Associated Proteins

KW - Odds Ratio

KW - P-Glycoprotein

KW - Time Factors

KW - Treatment Outcome

U2 - 10.1016/j.ejca.2013.06.017

DO - 10.1016/j.ejca.2013.06.017

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EP - 3516

JO - European Journal of Cancer

JF - European Journal of Cancer

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Middleton G, Brown S, Lowe C, Maughan T, Gwyther S, Oliver A et al. A randomised phase III trial of the pharmacokinetic biomodulation of irinotecan using oral ciclosporin in advanced colorectal cancer: results of the Panitumumab, Irinotecan & Ciclosporin in COLOrectal cancer therapy trial (PICCOLO). European Journal of Cancer. 2013 Nov;49(16):3507-16. doi: 10.1016/j.ejca.2013.06.017