Preclinical Pharmacokinetics and Dosimetry Studies of 124I/131I-CLR1404 for Treatment of Pediatric Solid Tumors in Murine Xenograft Models

Abstract

Pediatric cancer is the second leading cause of death for children between the ages of 5-14. For children diagnosed with metastatic or recurrent solid tumors, where the utility of external-beam radiotherapy is limited, the prognosis is particularly poor. The availability of tumor-targeting radiopharmaceuticals for molecular radiotherapy (MRT) has demonstrated improved outcomes in these patient populations, but options are nonexistent or limited for most pediatric solid tumors. 18-(p-iodophenyl) octadecyl phosphocholine (CLR1404) is a novel antitumor alkyl phospholipid ether analog that broadly targets cancer cells. In this study, we evaluated the in vivo pharmacokinetics of ¹²⁴I-CLR1404 (CLR 124) and estimated theranostic dosimetry for ¹³¹I-CLR1404 (CLR 131) MRT in murine xenograft models of the pediatric solid tumors’ neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma. Methods: Tumor bearing mice were imaged with microPET/CT to evaluate the whole-body distribution of CLR 124 and, correcting for differences in radioactive decay, predict that of CLR 131. Image volumes representing CLR 131 provided input for Geant4 Monte Carlo simulations to calculate subject-specific tumor dosimetry for CLR 131 MRT. Pharmacokinetics for CLR 131 were extrapolated to adult and pediatric humans to estimate normal tissue dosimetry. In neuroblastoma, a direct comparison of CLR 124 with ¹²⁴I-MIBG in an MIBG-avid model was performed. Results: In vivo pharmacokinetics of CLR 124 showed selective uptake and prolonged retention across all pediatric solid tumor models investigated. Subject-specific tumor dosimetry for CLR 131 MRT presents a correlative relationship with tumor-growth delay following CLR 131 MRT. Peak uptake of CLR 124 was, on average, 22% higher than ¹²⁴I-MIBG in a MIBG-avid neuroblastoma model. Conclusion: CLR1404 is a suitable theranostic scaffold for dosimetry and therapy with potentially broad applicability in pediatric oncology. Given the ongoing clinical trials for CLR 131 in adults, this data supports the development of pediatric clinical trials and provides detailed dosimetry that may lead to improved MRT treatment planning.