Preclinical pharmacokinetics and dosimetry studies of 124I/131I-CLR1404 for treatment of pediatric solid tumors in murine xenograft models

Ian R. Marsh, Joseph Grudzinski, Dana C. Baiu, Abigail Besemer, Reinier Hernandez, Justin J. Jeffery, Jamey P. Weichert, Mario Otto, Bryan P. Bednarz

Research output: Contribution to journalArticle

Abstract

Cancer is the second leading cause of death for children between the ages of 5 and 14 y. For children diagnosed with metastatic or recurrent solid tumors, for which 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)octadecylphosphocholine (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 small-animal PET/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-metaiodoben-zylguanidine (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 after CLR 131 MRT. Peak uptake of CLR 124 was, on average, 22% higher than that of 124I-MIBG in an 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, these data support the development of pediatric clinical trials and provide detailed dosimetry that may lead to improved MRT treatment planning.

Original languageEnglish (US)
Pages (from-to)1414-1420
Number of pages7
JournalJournal of Nuclear Medicine
Volume60
Issue number10
DOIs
StatePublished - Oct 1 2019

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Heterografts
Pharmacokinetics
Pediatrics
Radiotherapy
Neoplasms
Neuroblastoma
3-Iodobenzylguanidine
Therapeutics
Phospholipid Ethers
CLR1404
Clinical Trials
Ewing's Sarcoma
Second Primary Neoplasms
Radiopharmaceuticals
Rhabdomyosarcoma
Cause of Death
Growth

Keywords

  • CLR 131
  • CLR1404
  • Molecular radiotherapy
  • Pediatric cancer
  • Theranostic dosimetry

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

Preclinical pharmacokinetics and dosimetry studies of 124I/131I-CLR1404 for treatment of pediatric solid tumors in murine xenograft models. / Marsh, Ian R.; Grudzinski, Joseph; Baiu, Dana C.; Besemer, Abigail; Hernandez, Reinier; Jeffery, Justin J.; Weichert, Jamey P.; Otto, Mario; Bednarz, Bryan P.

In: Journal of Nuclear Medicine, Vol. 60, No. 10, 01.10.2019, p. 1414-1420.

Research output: Contribution to journalArticle

Marsh, Ian R. ; Grudzinski, Joseph ; Baiu, Dana C. ; Besemer, Abigail ; Hernandez, Reinier ; Jeffery, Justin J. ; Weichert, Jamey P. ; Otto, Mario ; Bednarz, Bryan P. / Preclinical pharmacokinetics and dosimetry studies of 124I/131I-CLR1404 for treatment of pediatric solid tumors in murine xenograft models. In: Journal of Nuclear Medicine. 2019 ; Vol. 60, No. 10. pp. 1414-1420.
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abstract = "Cancer is the second leading cause of death for children between the ages of 5 and 14 y. For children diagnosed with metastatic or recurrent solid tumors, for which 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)octadecylphosphocholine (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 small-animal PET/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-metaiodoben-zylguanidine (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 after CLR 131 MRT. Peak uptake of CLR 124 was, on average, 22{\%} higher than that of 124I-MIBG in an 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, these data support the development of pediatric clinical trials and provide detailed dosimetry that may lead to improved MRT treatment planning.",
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AU - Baiu, Dana C.

AU - Besemer, Abigail

AU - Hernandez, Reinier

AU - Jeffery, Justin J.

AU - Weichert, Jamey P.

AU - Otto, Mario

AU - Bednarz, Bryan P.

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KW - Pediatric cancer

KW - Theranostic dosimetry

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