Christof Rottenburger1, Guillaume P Nicolas1,2, Lisa McDougall1, Felix Kaul1,2, Michal Cachovan3, A Hans Vija4, Roger Schibli5, Susanne Geistlich6, Anne Schumann7, Tilman Rau8, Katharina Glatz9, Martin Behe6, Emanuel R Christ2,10, Damian Wild11,2. 1. Division of Nuclear Medicine, University Hospital Basel, Basel, Switzerland. 2. Center for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland. 3. Siemens Healthcare GmbH, Forchheim, Germany. 4. Molecular Imaging, Siemens Medical Solutions USA, Inc., Hoffman Estates, Illinois. 5. Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH, Zurich, Switzerland. 6. Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen, Switzerland. 7. 3B Pharmaceuticals GmbH, Berlin, Germany. 8. Institute of Pathology, University of Bern, Bern, Switzerland. 9. Institute of Pathology, University Hospital Basel, Basel, Switzerland; and. 10. Division of Endocrinology, Diabetology and Metabolism, University Hospital Basel, Basel, Switzerland. 11. Division of Nuclear Medicine, University Hospital Basel, Basel, Switzerland damian.wild@usb.ch.
Abstract
Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades, it has been known that the cholecystokinin 2 receptor is a promising target for the treatment of MTC with radiolabeled minigastrin analogs. Unfortunately, kidney toxicity has precluded their therapeutic application so far. In 6 consecutive patients, we evaluated with advanced 3-dimensional dosimetry whether improved minigastrin analog 177Lu-DOTA-(d-Glu)6-Ala-Tyr-Gly-Trp-Nle-Asp-PheNH2 (177Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received 2 injections of about 1 GBq (∼80 μg) of 177Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random crossover sequence to evaluate biodistribution, pharmacokinetics, and tumor and organ dosimetry. An electrocardiogram was obtained and blood count and blood chemistry were measured up to 12 wk after the administration of 177Lu-PP-F11N to assess safety. Results: In all patients, 177Lu-PP-F11N accumulation was visible in tumor tissue, stomach, and kidneys. Altogether, 13 tumors were eligible for dosimetry. The median absorbed doses for tumors, stomach, kidneys, and bone marrow were 0.88 (interquartile range [IQR]: 0.85-1.04), 0.42 (IQR: 0.25-1.01), 0.11 (IQR: 0.07-0.13), and 0.028 (IQR: 0.026-0.034) Gy/GBq, respectively. These doses resulted in median tumor-to-kidney dose ratios of 11.6 (IQR: 8.11-14.4) without SG and 13.0 (IQR: 10.2-18.6) with SG; these values were not significantly different (P = 1.0). The median tumor-to-stomach dose ratio was 3.34 (IQR: 1.14-4.70). Adverse reactions (mainly hypotension, flushing, and hypokalemia) were self-limiting and not higher than grade 1. Conclusion: 177Lu-PP-F11N accumulates specifically in MTC at a dose that is sufficient for a therapeutic approach. With a low kidney and bone marrow radiation dose, 177Lu-PP-F11N shows a promising biodistribution. The dose-limiting organ is most likely the stomach. Further clinical studies are necessary to evaluate the maximum tolerated dose and the efficacy of 177Lu-PP-F11N.
Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades, it has been known that the cholecystokinin 2 receptor is a promising target for the treatment of MTC with radiolabeled minigastrin analogs. Unfortunately, kidney toxicity has precluded their therapeutic application so far. In 6 consecutive patients, we evaluated with advanced 3-dimensional dosimetry whether improved minigastrin analog 177Lu-DOTA-(d-Glu)6-Ala-Tyr-Gly-Trp-Nle-Asp-PheNH2 (177Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods:Patients received 2 injections of about 1 GBq (∼80 μg) of 177Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random crossover sequence to evaluate biodistribution, pharmacokinetics, and tumor and organ dosimetry. An electrocardiogram was obtained and blood count and blood chemistry were measured up to 12 wk after the administration of 177Lu-PP-F11N to assess safety. Results: In all patients, 177Lu-PP-F11N accumulation was visible in tumor tissue, stomach, and kidneys. Altogether, 13 tumors were eligible for dosimetry. The median absorbed doses for tumors, stomach, kidneys, and bone marrow were 0.88 (interquartile range [IQR]: 0.85-1.04), 0.42 (IQR: 0.25-1.01), 0.11 (IQR: 0.07-0.13), and 0.028 (IQR: 0.026-0.034) Gy/GBq, respectively. These doses resulted in median tumor-to-kidney dose ratios of 11.6 (IQR: 8.11-14.4) without SG and 13.0 (IQR: 10.2-18.6) with SG; these values were not significantly different (P = 1.0). The median tumor-to-stomach dose ratio was 3.34 (IQR: 1.14-4.70). Adverse reactions (mainly hypotension, flushing, and hypokalemia) were self-limiting and not higher than grade 1. Conclusion:177Lu-PP-F11N accumulates specifically in MTC at a dose that is sufficient for a therapeutic approach. With a low kidney and bone marrow radiation dose, 177Lu-PP-F11N shows a promising biodistribution. The dose-limiting organ is most likely the stomach. Further clinical studies are necessary to evaluate the maximum tolerated dose and the efficacy of 177Lu-PP-F11N.
Authors: T D Barrett; G Lagaud; P Wagaman; J M Freedman; W Yan; L Andries; M C Rizzolio; M F Morton; N P Shankley Journal: Br J Pharmacol Date: 2012-07 Impact factor: 8.739
Authors: Maximilian Klingler; Dominik Summer; Christine Rangger; Roland Haubner; Julie Foster; Jane Sosabowski; Clemens Decristoforo; Irene Virgolini; Elisabeth von Guggenberg Journal: J Nucl Med Date: 2018-12-07 Impact factor: 10.057
Authors: Samuel A Wells; Sylvia L Asa; Henning Dralle; Rossella Elisei; Douglas B Evans; Robert F Gagel; Nancy Lee; Andreas Machens; Jeffrey F Moley; Furio Pacini; Friedhelm Raue; Karin Frank-Raue; Bruce Robinson; M Sara Rosenthal; Massimo Santoro; Martin Schlumberger; Manisha Shah; Steven G Waguespack Journal: Thyroid Date: 2015-06 Impact factor: 6.568
Authors: Petra Kolenc-Peitl; Rosalba Mansi; MariaLuisa Tamma; Tanja Gmeiner-Stopar; Marija Sollner-Dolenc; Beatrice Waser; Richard P Baum; Jean Claude Reubi; Helmut R Maecke Journal: J Med Chem Date: 2011-04-01 Impact factor: 7.446
Authors: Meltem Ocak; Anna Helbok; Christine Rangger; Petra Kolenc Peitl; Berthold A Nock; Giancarlo Morelli; Annemarie Eek; Jane K Sosabowski; Wout A P Breeman; Jean Claude Reubi; Clemens Decristoforo Journal: Eur J Nucl Med Mol Imaging Date: 2011-04-29 Impact factor: 9.236
Authors: Peter Laverman; Lieke Joosten; Annemarie Eek; Susan Roosenburg; Petra Kolenc Peitl; Theodosia Maina; Helmut Mäcke; Luigi Aloj; Elisabeth von Guggenberg; Jane K Sosabowski; Marion de Jong; Jean-Claude Reubi; Wim J G Oyen; Otto C Boerman Journal: Eur J Nucl Med Mol Imaging Date: 2011-04-02 Impact factor: 9.236
Authors: Maximilian Klingler; Anton A Hörmann; Christine Rangger; Laurence Desrues; Hélène Castel; Pierrick Gandolfo; Elisabeth von Guggenberg Journal: J Med Chem Date: 2020-11-23 Impact factor: 7.446
Authors: Anton A Hörmann; Maximilian Klingler; Christine Rangger; Christian Mair; Clemens Decristoforo; Christian Uprimny; Irene J Virgolini; Elisabeth von Guggenberg Journal: Pharmaceuticals (Basel) Date: 2021-06-16
Authors: Anton Amadeus Hörmann; Maximilian Klingler; Maliheh Rezaeianpour; Nikolas Hörmann; Ronald Gust; Soraya Shahhosseini; Elisabeth von Guggenberg Journal: Molecules Date: 2020-10-08 Impact factor: 4.411
Authors: Michal Grzmil; Yun Qin; Carina Schleuniger; Stephan Frank; Stefan Imobersteg; Alain Blanc; Martin Spillmann; Philipp Berger; Roger Schibli; Martin Behe Journal: Theranostics Date: 2020-08-29 Impact factor: 11.556
Authors: Michal Grzmil; Stefan Imobersteg; Alain Blanc; Stephan Frank; Roger Schibli; Martin P Béhé Journal: Pharmaceutics Date: 2021-12-15 Impact factor: 6.321