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Open Access 01-12-2020 | Positron Emission Tomography | Original research

Radiation dosimetry of ¹⁸F-AzaFol: A first in-human use of a folate receptor PET tracer

Authors: Silvano Gnesin, Joachim Müller, Irene A. Burger, Alexander Meisel, Marco Siano, Martin Früh, Matthias Choschzick, Cristina Müller, Roger Schibli, Simon M. Ametamey, Philipp A. Kaufmann, Valerie Treyer, John O. Prior, Niklaus Schaefer

Published in: EJNMMI Research | Issue 1/2020

Abstract

Background

The folate receptor alpha (FRα) is an interesting target for imaging and therapy of different cancers. We present the first in-human radiation dosimetry and radiation safety results acquired within a prospective, multicentric trial (NCT03242993) evaluating the ¹⁸F-AzaFol (3′-aza-2′-[¹⁸F]fluorofolic acid) as the first clinically assessed PET tracer targeting the FRα.

Material and methods

Six eligible patients presented a histologically confirmed adenocarcinoma of the lung with measurable lesions (≥ 10 mm according to RECIST 1.1). TOF-PET images were acquired at 3, 11, 18, 30, 40, 50, and 60 min after the intravenous injection of 327 MBq (range 299–399 MBq) of ¹⁸F-AzaFol to establish dosimetry. Organ absorbed doses (AD), tumor AD, and patient effective doses (E) were assessed using the OLINDA/EXM v.2.0 software and compared with pre-clinical results.

Results

No serious related adverse events were observed. The highest AD were in the liver, the kidneys, the urinary bladder, and the spleen (51.9, 45.8, 39.1, and 35.4 μGy/MBq, respectively). Estimated patient and gender-averaged E were 18.0 ± 2.6 and 19.7 ± 1.4 μSv/MBq, respectively. E in-human exceeded the value of 14.0 μSv/MBq extrapolated from pre-clinical data. Average tumor AD was 34.8 μGy/MBq (range 13.6–60.5 μGy/MBq).

Conclusions

¹⁸F-Azafol is a PET agent with favorable dosimetric properties and a reasonable radiation dose burden for patients which merits further evaluation to assess its performance.

Trial registration

ClinicalTrial.gov, NCT03242993, posted on August 8, 2017

Available only for authorised users

Assaraf YG, Leamon CP, Reddy JA. The folate receptor as a rational therapeutic target for personalized cancer treatment. Drug Resist Updat. 2014;17:89–95. https://doi.org/10.1016/j.drup.2014.10.002.CrossRefPubMed

Cheung A, Bax HJ, Josephs DH, Ilieva KM, Pellizzari G, Opzoomer J, et al. Targeting folate receptor alpha for cancer treatment. Oncotarget. 2016;7:52553–74. https://doi.org/10.18632/oncotarget.9651.CrossRefPubMedPubMedCentral

Teng L, Xie J, Teng L, Lee RJ. Clinical translation of folate receptor-targeted therapeutics. Expert Opin Drug Deliv. 2012;9:901–8. https://doi.org/10.1517/17425247.2012.694863.CrossRefPubMed

Vergote I, Armstrong D, Scambia G, Teneriello M, Sehouli J, Schweizer C, et al. A randomized, double-blind, placebo-controlled, phase III study to assess efficacy and safety of weekly farletuzumab in combination with carboplatin and taxane in patients with ovarian cancer in first platinum-sensitive relapse. J Clin Oncol. 2016;34:2271–8. https://doi.org/10.1200/JCO.2015.63.2596.CrossRefPubMed

Oza AM, Vergote IB, Gilbert LG, Ghatage P, Lisyankaya A, et al. A randomized double-blind phase III trial comparing vintafolide (EC145) and pegylated liposomal doxorubicin (PLD/Doxil®/Caelyx®) in combination versus PLD in participants with platinum-resistant ovarian cancer (PROCEED) (NCT01170650). Gynecologic Oncology. 2015;137:5–6. https://doi.org/10.1016/j.ygyno.2015.01.010.CrossRef

Filss C, Heinzel A, Miiller B, Vogg ATJ, Langen KJ, Mottaghy FM. Relevant tumor sink effect in prostate cancer patients receiving 177Lu-PSMA-617 radioligand therapy. Nuklearmedizin. 2018;57:19–25. https://doi.org/10.3413/Nukmed-0937-17-10.CrossRefPubMed

Fernandez M, Javaid F, Chudasama V. Advances in targeting the folate receptor in the treatment/imaging of cancers. Chem Sci. 2018;9:790–810. https://doi.org/10.1039/c7sc04004k.CrossRefPubMed

Morris RT, Joyrich RN, Naumann RW, Shah NP, Maurer AH, Strauss HW, et al. Phase II study of treatment of advanced ovarian cancer with folate-receptor-targeted therapeutic (vintafolide) and companion SPECT-based imaging agent (99mTc-etarfolatide). Ann Oncol. 2014;25:852–8. https://doi.org/10.1093/annonc/mdu024.CrossRefPubMed

Brand C, Longo VA, Groaning M, Weber WA, Reiner T. Development of a new folate-derived Ga-68-based PET imaging agent. Mol Imaging Biol. 2017;19:754–61. https://doi.org/10.1007/s11307-017-1049-y.CrossRefPubMedPubMedCentral

10.

Muller C. Folate-based radiotracers for PET imaging--update and perspectives. Molecules. 2013;18:5005–31. https://doi.org/10.3390/molecules18055005.CrossRefPubMedPubMedCentral

11.

Ross TL, Honer M, Muller C, Groehn V, Schibli R, Ametamey SM. A new 18F-labeled folic acid derivative with improved properties for the PET imaging of folate receptor-positive tumors. J Nucl Med. 2010;51:1756–62. https://doi.org/10.2967/jnumed.110.079756.CrossRefPubMed

12.

Betzel T, Muller C, Groehn V, Muller A, Reber J, Fischer CR, et al. Radiosynthesis and preclinical evaluation of 3'-Aza-2'-[(18)F]fluorofolic acid: a novel PET radiotracer for folate receptor targeting. Bioconjug Chem. 2013;24:205–14. https://doi.org/10.1021/bc300483a.CrossRefPubMed

13.

Nishino M, Jagannathan JP, Ramaiya NH, Van den Abbeele AD. Revised RECIST guideline version 1.1: what oncologists want to know and what radiologists need to know. AJR Am J Roentgenol. 2010;195:281–9. https://doi.org/10.2214/AJR.09.4110.CrossRefPubMed

14.

Gnesin S, Cicone F, Mitsakis P, Van der Gucht A, Baechler S, Miralbell R, et al. First in-human radiation dosimetry of the gastrin-releasing peptide (GRP) receptor antagonist (68)Ga-NODAGA-MJ9. EJNMMI Res. 2018;8:108. https://doi.org/10.1186/s13550-018-0462-9.CrossRefPubMedPubMedCentral

15.

Stabin MG, Siegel JA. RADAR dose estimate report: a compendium of radiopharmaceutical dose estimates based on OLINDA/EXM version 2.0. J Nucl Med. 2018;59:154–60. https://doi.org/10.2967/jnumed.117.196261.CrossRefPubMed

16.

Segars JP. Development and application of the new dynamic NURBS-based cardiac-torso (NCAT) phantom [dissertation] In: University of North Carolina; 2001.

17.

Basic anatomical and physiological data for use in radiological protection: reference values. A report of age- and gender-related differences in the anatomical and physiological characteristics of reference individuals. ICRP Publication 89. Ann ICRP. 2002;32:5-265.

18.

The 2007 Recommendations of the International Commission on Radiological Protection. ICRP publication 103. Ann ICRP. 2007;37:1-332. doi:https://doi.org/10.1016/j.icrp.2007.10.003.

19.

Amato E, Cicone F, Auditore L, Baldari S, Prior JO, Gnesin S. A Monte Carlo model for the internal dosimetry of choroid plexuses in nuclear medicine procedures. Phys Med. 2018;49:52–7. https://doi.org/10.1016/j.ejmp.2018.05.005.CrossRefPubMed

20.

Gnesin S, Mitsakis P, Cicone F, Deshayes E, Dunet V, Gallino AF, et al. First in-human radiation dosimetry of (68)Ga-NODAGA-RGDyK. EJNMMI Res. 2017;7:43. https://doi.org/10.1186/s13550-017-0288-x.CrossRefPubMedPubMedCentral

21.

Huang B, Law MW, Khong PL. Whole-body PET/CT scanning: estimation of radiation dose and cancer risk. Radiology. 2009;251:166–74. https://doi.org/10.1148/radiol.2511081300.CrossRefPubMed

22.

Icrp. Radiation dose to patients from radiopharmaceuticals. Addendum 3 to ICRP Publication 53. ICRP Publication 106. Approved by the Commission in October 2007. Ann ICRP. 2008;38:1–197. https://doi.org/10.1016/j.icrp.2008.08.003.CrossRefPubMed

23.

Yamada Y, Nakatani H, Yanaihara H, Omote M. Phase I clinical trial of 99mTc-etarfolatide, an imaging agent for folate receptor in healthy Japanese adults. Ann Nucl Med. 2015;29:792–8. https://doi.org/10.1007/s12149-015-1006-2.CrossRefPubMed

24.

Balashova OA, Visina O, Borodinsky LN. Folate action in nervous system development and disease. Dev Neurobiol. 2018;78:391–402. https://doi.org/10.1002/dneu.22579.CrossRefPubMedPubMedCentral

25.

Wollack JB, Makori B, Ahlawat S, Koneru R, Picinich SC, Smith A, et al. Characterization of folate uptake by choroid plexus epithelial cells in a rat primary culture model. J Neurochem. 2008;104:1494–503. https://doi.org/10.1111/j.1471-4159.2007.05095.x.CrossRefPubMed

26.

Grapp M, Wrede A, Schweizer M, Huwel S, Galla HJ, Snaidero N, et al. Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma. Nat Commun. 2013;4:2123. https://doi.org/10.1038/ncomms3123.CrossRefPubMed

27.

Patrick TA, Kranz DM, van Dyke TA, Roy EJ. Folate receptors as potential therapeutic targets in choroid plexus tumors of SV40 transgenic mice. J Neurooncol. 1997;32:111–23.CrossRef

28.

Sakata M, Oda K, Toyohara J, Ishii K, Nariai T, Ishiwata K. Direct comparison of radiation dosimetry of six PET tracers using human whole-body imaging and murine biodistribution studies. Ann Nucl Med. 2013;27:285–96. https://doi.org/10.1007/s12149-013-0685-9.CrossRefPubMed

29.

Bencherif B, Endres CJ, Musachio JL, Villalobos A, Hilton J, Scheffel U, et al. PET imaging of brain acetylcholinesterase using [11C]CP-126,998, a brain selective enzyme inhibitor. Synapse. 2002;45:1–9. https://doi.org/10.1002/syn.10072.CrossRefPubMed

30.

Tolvanen T, Yli-Kerttula T, Ujula T, Autio A, Lehikoinen P, Minn H, et al. Biodistribution and radiation dosimetry of [(11)C]choline: a comparison between rat and human data. Eur J Nucl Med Mol Imaging. 2010;37:874–83. https://doi.org/10.1007/s00259-009-1346-z.CrossRefPubMed

31.

Lin JH. Species similarities and differences in pharmacokinetics. Drug Metab Dispos. 1995;23:1008–21.PubMed

32.

Lynn RC, Poussin M, Kalota A, Feng Y, Low PS, Dimitrov DS, et al. Targeting of folate receptor beta on acute myeloid leukemia blasts with chimeric antigen receptor-expressing T cells. Blood. 2015;125:3466–76. https://doi.org/10.1182/blood-2014-11-612721.CrossRefPubMedPubMedCentral

33.

Song DG, Ye Q, Poussin M, Chacon JA, Figini M, Powell DJ Jr. Effective adoptive immunotherapy of triple-negative breast cancer by folate receptor-alpha redirected CAR T cells is influenced by surface antigen expression level. J Hematol Oncol. 2016;9:56. https://doi.org/10.1186/s13045-016-0285-y.CrossRefPubMedPubMedCentral

34.

Kim M, Pyo S, Kang CH, Lee CO, Lee HK, Choi SU, et al. Folate receptor 1 (FOLR1) targeted chimeric antigen receptor (CAR) T cells for the treatment of gastric cancer. PLoS One. 2018;13:e0198347. https://doi.org/10.1371/journal.pone.0198347.CrossRefPubMedPubMedCentral

35.

Fan CA, Reader J, Roque DM. Review of immune therapies targeting ovarian cancer. Curr Treat Options Oncol. 2018;19:74. https://doi.org/10.1007/s11864-018-0584-3.CrossRefPubMed

36.

Parker N, Turk MJ, Westrick E, Lewis JD, Low PS, Leamon CP. Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Anal Biochem. 2005;338:284–93. https://doi.org/10.1016/j.ab.2004.12.026.CrossRefPubMed

Title: Radiation dosimetry of 18F-AzaFol: A first in-human use of a folate receptor PET tracer
Authors: Silvano Gnesin
Joachim Müller
Irene A. Burger
Alexander Meisel
Marco Siano
Martin Früh
Matthias Choschzick
Cristina Müller
Roger Schibli
Simon M. Ametamey
Philipp A. Kaufmann
Valerie Treyer
John O. Prior
Niklaus Schaefer
Publication date: 01-12-2020
Publisher: Springer Berlin Heidelberg
Keyword: Positron Emission Tomography
Published in: EJNMMI Research / Issue 1/2020
Electronic ISSN: 2191-219X
DOI: https://doi.org/10.1186/s13550-020-00624-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Radiation dosimetry of ¹⁸F-AzaFol: A first in-human use of a folate receptor PET tracer

Abstract

Background

Material and methods

Results

Conclusions

Trial registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Material and methods

Results

Conclusions

Trial registration

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