Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study.
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/m2free 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 andP< 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 (Spearmanρ= 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.
Virginia G Piper Cancer Center, Honor Healthcare, Scottsdale, Arizona. Ramanathan.ramesh@mayo.edu Sklinz@merrimack.com.|Translational Genomics Research Institute, Phoenix, Arizona.
Ramesh K
RK
Ramanathan
Virginia G Piper Cancer Center, Honor Healthcare, Scottsdale, Arizona.|Imaging Endpoints, Scottsdale, Arizona.
Ronald L
RL
Korn
Moffitt Cancer Center, Tampa, Florida.
Natarajan
N
Raghunand
Virginia G Piper Cancer Center, Honor Healthcare, Scottsdale, Arizona.
Jasgit C
JC
Sachdev
Virginia G Piper Cancer Center, Honor Healthcare, Scottsdale, Arizona.|Imaging Endpoints, Scottsdale, Arizona.
Ronald G
RG
Newbold
Virginia G Piper Cancer Center, Honor Healthcare, Scottsdale, Arizona.
Gayle
G
Jameson
Roswell Park Cancer Institute, Buffalo, New York.
Gerald J
GJ
Fetterly
Roswell Park Cancer Institute, Buffalo, New York.
Joshua
J
Prey
Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts. Ramanathan.ramesh@mayo.edu Sklinz@merrimack.com.
Stephan G
SG
Klinz
Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts.
Jaeyeon
J
Kim
Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts.
Jason
J
Cain
Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts.
Bart S
BS
Hendriks
Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts.
Daryl C
DC
Drummond
Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts.
Eliel
E
Bayever
Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts.
Jonathan B
JB
Fitzgerald
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry; D018572:Disease-Free Survival; D005260:Female; D052203:Ferrosoferric Oxide / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D006801:Humans; D000077146:Irinotecan; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D010865:Pilot Projects
D008081:Liposomes; D000077146:Irinotecan; D052203:Ferrosoferric Oxide; D002166:Camptothecin