Correlation between ferumoxytol uptake in tumor lesions by MRI and response to nanoliposomal irinotecan in patients with advanced solid tumors: A pilot study

Ramesk K Ramanathan, Ronald L. Korn, Natarajan Raghunand, Jasgit C. Sachdev, Ronald G. Newbold, Gayle Jameson, Gerald J. Fetterly, Joshua Prey, Stephan G. Klinz, Jaeyeon Kim, Jason Cain, Bart S. Hendriks, Daryl C. Drummond, Eliel Bayever, Jonathan B. Fitzgerald

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Abstract

Purpose: To determine whether deposition characteristics of ferumoxytol (FMX) iron nanoparticles in tumors, identified by quantitative MRI, may predict tumor lesion response to nanoliposomal irinotecan (nal-IRI). Experimental Design: Eligible patients with previously treated solid tumors had FMX-MRI scans before and following (1, 24, and 72 hours) FMX injection. After MRI acquisition, R2 signal was used to calculate FMX levels in plasma, reference tissue, and tumor lesions by comparison with a phantom-based standard curve. Patients then received nal-IRI (70 mg/m2 free base strength) biweekly until progression. Two percutaneous core biopsies were collected from selected tumor lesions 72 hours after FMX or nal-IRI. Results: Iron particle levels were quantified by FMX-MRI in plasma, reference tissues, and tumor lesions in 13 of 15 eligible patients. On the basis of a mechanistic pharmacokinetic model, tissue permeability to FMX correlated with early FMX-MRI signals at 1 and 24 hours, while FMX tissue binding contributed at 72 hours. Higher FMX levels (ranked relative to median value of multiple evaluable lesions from 9 patients) were significantly associated with reduction in lesion size by RECIST v1.1 at early time points (P < 0.001 at 1 hour and P < 0.003 at 24 hours FMX-MRI, one-way ANOVA). No association was observed with post-FMX levels at 72 hours. Irinotecan drug levels in lesions correlated with patient's time on treatment (Spearman r ¼ 0.7824; P ¼ 0.0016). Conclusions: Correlation between FMX levels in tumor lesions and nal-IRI activity suggests that lesion permeability to FMX and subsequent tumor uptake may be a useful noninvasive and predictive biomarker for nal-IRI response in patients with solid tumors.

Original languageEnglish (US)
Pages (from-to)3638-3648
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number14
DOIs
StatePublished - Jul 15 2017

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irinotecan
Ferrosoferric Oxide
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Correlation between ferumoxytol uptake in tumor lesions by MRI and response to nanoliposomal irinotecan in patients with advanced solid tumors : A pilot study. / Ramanathan, Ramesk K; Korn, Ronald L.; Raghunand, Natarajan; Sachdev, Jasgit C.; Newbold, Ronald G.; Jameson, Gayle; Fetterly, Gerald J.; Prey, Joshua; Klinz, Stephan G.; Kim, Jaeyeon; Cain, Jason; Hendriks, Bart S.; Drummond, Daryl C.; Bayever, Eliel; Fitzgerald, Jonathan B.

In: Clinical Cancer Research, Vol. 23, No. 14, 15.07.2017, p. 3638-3648.

Research output: Contribution to journalArticle

Ramanathan, RK, Korn, RL, Raghunand, N, Sachdev, JC, Newbold, RG, Jameson, G, Fetterly, GJ, Prey, J, Klinz, SG, Kim, J, Cain, J, Hendriks, BS, Drummond, DC, Bayever, E & Fitzgerald, JB 2017, 'Correlation between ferumoxytol uptake in tumor lesions by MRI and response to nanoliposomal irinotecan in patients with advanced solid tumors: A pilot study', Clinical Cancer Research, vol. 23, no. 14, pp. 3638-3648. https://doi.org/10.1158/1078-0432.CCR-16-1990
Ramanathan, Ramesk K ; Korn, Ronald L. ; Raghunand, Natarajan ; Sachdev, Jasgit C. ; Newbold, Ronald G. ; Jameson, Gayle ; Fetterly, Gerald J. ; Prey, Joshua ; Klinz, Stephan G. ; Kim, Jaeyeon ; Cain, Jason ; Hendriks, Bart S. ; Drummond, Daryl C. ; Bayever, Eliel ; Fitzgerald, Jonathan B. / Correlation between ferumoxytol uptake in tumor lesions by MRI and response to nanoliposomal irinotecan in patients with advanced solid tumors : A pilot study. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 14. pp. 3638-3648.
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abstract = "Purpose: To determine whether deposition characteristics of ferumoxytol (FMX) iron nanoparticles in tumors, identified by quantitative MRI, may predict tumor lesion response to nanoliposomal irinotecan (nal-IRI). Experimental Design: Eligible patients with previously treated solid tumors had FMX-MRI scans before and following (1, 24, and 72 hours) FMX injection. After MRI acquisition, R2 signal was used to calculate FMX levels in plasma, reference tissue, and tumor lesions by comparison with a phantom-based standard curve. Patients then received nal-IRI (70 mg/m2 free base strength) biweekly until progression. Two percutaneous core biopsies were collected from selected tumor lesions 72 hours after FMX or nal-IRI. Results: Iron particle levels were quantified by FMX-MRI in plasma, reference tissues, and tumor lesions in 13 of 15 eligible patients. On the basis of a mechanistic pharmacokinetic model, tissue permeability to FMX correlated with early FMX-MRI signals at 1 and 24 hours, while FMX tissue binding contributed at 72 hours. Higher FMX levels (ranked relative to median value of multiple evaluable lesions from 9 patients) were significantly associated with reduction in lesion size by RECIST v1.1 at early time points (P < 0.001 at 1 hour and P < 0.003 at 24 hours FMX-MRI, one-way ANOVA). No association was observed with post-FMX levels at 72 hours. Irinotecan drug levels in lesions correlated with patient's time on treatment (Spearman r ¼ 0.7824; P ¼ 0.0016). Conclusions: Correlation between FMX levels in tumor lesions and nal-IRI activity suggests that lesion permeability to FMX and subsequent tumor uptake may be a useful noninvasive and predictive biomarker for nal-IRI response in patients with solid tumors.",
author = "Ramanathan, {Ramesk K} and Korn, {Ronald L.} and Natarajan Raghunand and Sachdev, {Jasgit C.} and Newbold, {Ronald G.} and Gayle Jameson and Fetterly, {Gerald J.} and Joshua Prey and Klinz, {Stephan G.} and Jaeyeon Kim and Jason Cain and Hendriks, {Bart S.} and Drummond, {Daryl C.} and Eliel Bayever and Fitzgerald, {Jonathan B.}",
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T1 - Correlation between ferumoxytol uptake in tumor lesions by MRI and response to nanoliposomal irinotecan in patients with advanced solid tumors

T2 - A pilot study

AU - Ramanathan, Ramesk K

AU - Korn, Ronald L.

AU - Raghunand, Natarajan

AU - Sachdev, Jasgit C.

AU - Newbold, Ronald G.

AU - Jameson, Gayle

AU - Fetterly, Gerald J.

AU - Prey, Joshua

AU - Klinz, Stephan G.

AU - Kim, Jaeyeon

AU - Cain, Jason

AU - Hendriks, Bart S.

AU - Drummond, Daryl C.

AU - Bayever, Eliel

AU - Fitzgerald, Jonathan B.

PY - 2017/7/15

Y1 - 2017/7/15

N2 - Purpose: To determine whether deposition characteristics of ferumoxytol (FMX) iron nanoparticles in tumors, identified by quantitative MRI, may predict tumor lesion response to nanoliposomal irinotecan (nal-IRI). Experimental Design: Eligible patients with previously treated solid tumors had FMX-MRI scans before and following (1, 24, and 72 hours) FMX injection. After MRI acquisition, R2 signal was used to calculate FMX levels in plasma, reference tissue, and tumor lesions by comparison with a phantom-based standard curve. Patients then received nal-IRI (70 mg/m2 free base strength) biweekly until progression. Two percutaneous core biopsies were collected from selected tumor lesions 72 hours after FMX or nal-IRI. Results: Iron particle levels were quantified by FMX-MRI in plasma, reference tissues, and tumor lesions in 13 of 15 eligible patients. On the basis of a mechanistic pharmacokinetic model, tissue permeability to FMX correlated with early FMX-MRI signals at 1 and 24 hours, while FMX tissue binding contributed at 72 hours. Higher FMX levels (ranked relative to median value of multiple evaluable lesions from 9 patients) were significantly associated with reduction in lesion size by RECIST v1.1 at early time points (P < 0.001 at 1 hour and P < 0.003 at 24 hours FMX-MRI, one-way ANOVA). No association was observed with post-FMX levels at 72 hours. Irinotecan drug levels in lesions correlated with patient's time on treatment (Spearman r ¼ 0.7824; P ¼ 0.0016). Conclusions: Correlation between FMX levels in tumor lesions and nal-IRI activity suggests that lesion permeability to FMX and subsequent tumor uptake may be a useful noninvasive and predictive biomarker for nal-IRI response in patients with solid tumors.

AB - Purpose: To determine whether deposition characteristics of ferumoxytol (FMX) iron nanoparticles in tumors, identified by quantitative MRI, may predict tumor lesion response to nanoliposomal irinotecan (nal-IRI). Experimental Design: Eligible patients with previously treated solid tumors had FMX-MRI scans before and following (1, 24, and 72 hours) FMX injection. After MRI acquisition, R2 signal was used to calculate FMX levels in plasma, reference tissue, and tumor lesions by comparison with a phantom-based standard curve. Patients then received nal-IRI (70 mg/m2 free base strength) biweekly until progression. Two percutaneous core biopsies were collected from selected tumor lesions 72 hours after FMX or nal-IRI. Results: Iron particle levels were quantified by FMX-MRI in plasma, reference tissues, and tumor lesions in 13 of 15 eligible patients. On the basis of a mechanistic pharmacokinetic model, tissue permeability to FMX correlated with early FMX-MRI signals at 1 and 24 hours, while FMX tissue binding contributed at 72 hours. Higher FMX levels (ranked relative to median value of multiple evaluable lesions from 9 patients) were significantly associated with reduction in lesion size by RECIST v1.1 at early time points (P < 0.001 at 1 hour and P < 0.003 at 24 hours FMX-MRI, one-way ANOVA). No association was observed with post-FMX levels at 72 hours. Irinotecan drug levels in lesions correlated with patient's time on treatment (Spearman r ¼ 0.7824; P ¼ 0.0016). Conclusions: Correlation between FMX levels in tumor lesions and nal-IRI activity suggests that lesion permeability to FMX and subsequent tumor uptake may be a useful noninvasive and predictive biomarker for nal-IRI response in patients with solid tumors.

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