Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study

• Published in: Clinical cancer research Vol. 23; no. 14; pp. 3638 - 3648
• Main Authors: Ramanathan, Ramesh 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.
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 15.07.2017
• Subjects: Adult; Aged; Aged, 80 and over; Biomarkers; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - blood; Camptothecin - chemistry; Cancer; Correlation; Disease-Free Survival; Experimental design; Female; Ferrosoferric Oxide - administration & dosage; Ferrosoferric Oxide - blood; Ferrosoferric Oxide - chemistry; Humans; Irinotecan; Iron; Lesions; Liposomes - administration & dosage; Liposomes - chemistry; Magnetic Resonance Imaging; Male; Middle Aged; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Neoplasms - diagnostic imaging; Neoplasms - drug therapy; Neoplasms - pathology; Patients; Permeability; Pharmacology; Pilot Projects; Solid tumors; Tissues; Tumors; Variance analysis
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-1990

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 ρ = 0.7824; P = 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. Clin Cancer Res; 23(14); 3638–48. ©2017 AACR.