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

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, 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

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.

Keywords: 18F-Azafol; Choroid plexuses; Dosimetry; FOLR1; FRalpha; FRα; Folate receptor; Imaging; Lung cancer; OLINDA/EXM; Positron emission tomography (PET).

Conflict of interest statement

PD Dr. Cristina Müller, Prof. Roger Schibli, and Prof. Simon M. Ametamey are co-inventors of the patent no. WO2013167653 used in this study but had no access to imaging data.

Figures

Fig. 1
Fig. 1
Example of maximum intensity projections 3, 11, 18, 30, 40, and 60 min post-tracer administration (p.a) showing in-patient 18F-Azafol activity distribution
Fig. 2
Fig. 2
Typical 18F-AzaFol uptake pattern in the choroid plexuses (lateral ventricles) for a representative patient at 30 min post-administration
Fig. 3
Fig. 3
Biological organ kinetic of 18F-AzaFol corrected for 18F physical decay. Color bars represent the average percent of injected activity per gram of tissue (%IA/g) ± 1SD, for each time point
Fig. 4
Fig. 4
Mean nA ± SD (average values and SD evaluated across the 6 patients), for considered source organs. Mono- and bi-exponential fits of experimental data are displayed in addition to the tail according to pure physical decay to infinity for t > 60 min. For sake of visibility, the time base in each source organ graph was restricted to three times the physical half-life of 18F

References

    1. 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. doi: 10.1016/j.drup.2014.10.002.
    1. Cheung A, Bax HJ, Josephs DH, Ilieva KM, Pellizzari G, Opzoomer J, et al. Targeting folate receptor alpha for cancer treatment. Oncotarget. 2016;7:52553–52574. doi: 10.18632/oncotarget.9651.
    1. Teng L, Xie J, Teng L, Lee RJ. Clinical translation of folate receptor-targeted therapeutics. Expert Opin Drug Deliv. 2012;9:901–908. doi: 10.1517/17425247.2012.694863.
    1. 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;34:2271–2278. doi: 10.1200/JCO.2015.63.2596.
    1. 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. doi: 10.1016/j.ygyno.2015.01.010.
    1. 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. doi: 10.3413/Nukmed-0937-17-10.
    1. Fernandez M, Javaid F, Chudasama V. Advances in targeting the folate receptor in the treatment/imaging of cancers. Chem Sci. 2018;9:790–810. doi: 10.1039/c7sc04004k.
    1. 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;25:852–858. doi: 10.1093/annonc/mdu024.
    1. 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;19:754–761. doi: 10.1007/s11307-017-1049-y.
    1. Muller C. Folate-based radiotracers for PET imaging--update and perspectives. Molecules. 2013;18:5005–5031. doi: 10.3390/molecules18055005.
    1. 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;51:1756–1762. doi: 10.2967/jnumed.110.079756.
    1. 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;24:205–214. doi: 10.1021/bc300483a.
    1. 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;195:281–289. doi: 10.2214/AJR.09.4110.
    1. 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. doi: 10.1186/s13550-018-0462-9.
    1. 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;59:154–160. doi: 10.2967/jnumed.117.196261.
    1. Segars JP. Development and application of the new dynamic NURBS-based cardiac-torso (NCAT) phantom [dissertation] In: University of North Carolina. 2001.
    1. 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.
    1. The 2007 Recommendations of the International Commission on Radiological Protection. ICRP publication 103. Ann ICRP. 2007;37:1-332. doi:10.1016/j.icrp.2007.10.003.
    1. 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;49:52–57. doi: 10.1016/j.ejmp.2018.05.005.
    1. 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. doi: 10.1186/s13550-017-0288-x.
    1. Huang B, Law MW, Khong PL. Whole-body PET/CT scanning: estimation of radiation dose and cancer risk. Radiology. 2009;251:166–174. doi: 10.1148/radiol.2511081300.
    1. 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. doi: 10.1016/j.icrp.2008.08.003.
    1. 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;29:792–798. doi: 10.1007/s12149-015-1006-2.
    1. Balashova OA, Visina O, Borodinsky LN. Folate action in nervous system development and disease. Dev Neurobiol. 2018;78:391–402. doi: 10.1002/dneu.22579.
    1. 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;104:1494–1503. doi: 10.1111/j.1471-4159.2007.05095.x.
    1. 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. doi: 10.1038/ncomms3123.
    1. 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;32:111–123. doi: 10.1023/A:1005713115147.
    1. 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;27:285–296. doi: 10.1007/s12149-013-0685-9.
    1. 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. doi: 10.1002/syn.10072.
    1. 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;37:874–883. doi: 10.1007/s00259-009-1346-z.
    1. Lin JH. Species similarities and differences in pharmacokinetics. Drug Metab Dispos. 1995;23:1008–1021.
    1. 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;125:3466–3476. doi: 10.1182/blood-2014-11-612721.
    1. 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. doi: 10.1186/s13045-016-0285-y.
    1. 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. doi: 10.1371/journal.pone.0198347.
    1. Fan CA, Reader J, Roque DM. Review of immune therapies targeting ovarian cancer. Curr Treat Options Oncol. 2018;19:74. doi: 10.1007/s11864-018-0584-3.
    1. 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;338:284–293. doi: 10.1016/j.ab.2004.12.026.

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