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Combined beta- and Auger electron therapy using a novel somatostatin receptor subtype 2 antagonist labelled with terbium-161 (161Tb-DOTA-LM3) - a phase 0/ phase I study

English title Combined beta- and Auger electron therapy using a novel somatostatin receptor subtype 2 antagonist labelled with terbium-161 (161Tb-DOTA-LM3) - a phase 0/ phase I study
Applicant Wild Damian
Number 205070
Funding scheme Project funding
Research institution Klinik für Radiologie und Nuklearmedizin Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Clinical Cancer Research
Start/End 01.01.2022 - 31.12.2025
Approved amount 794'877.00
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All Disciplines (2)

Discipline
Clinical Cancer Research
Experimental Cancer Research

Keywords (6)

Peptide receptor radionuclide therapy; First-in-human study; Neuroendocrine tumours; Somatostatin receptor antagonist; Terbium-161; Somatostatin receptor subtype 2

Lay Summary (German)

Lead
Therapie neuroendokriner Tumore mit 161Tb-DOTA-LM3: beta+ Studie
Lay summary

Neuroendokrine Tumore (NET) sind eine Gruppe von bösartigen Tumoren, die von neuroendokrinen Zellen ausgehen und häufig im Darm, Bauchspeicheldrüse und Lunge vorkommen. Obwohl es sich bei NET um seltene Tumoren handelt, hat die Häufigkeit in den letzten Jahrzehnten deutlich zugenommen, sodass aktuell etwa 1 von 2000 Personen an einem Neuroendokrinen Tumor leidet.

Die Überexpression des Somatostatinrezeptor-Subtyps 2 (SST2) ist ein Merkmal der NET und kann für die Behandlung dieser Tumoren mittels Peptidrezeptor-Radionuklidtherapie (PRRT) genutzt werden. Obwohl die PRRT mit radioaktiv markierten Substanzen wie 177Lu-DOTATOC und 177Lu-DOTATATE zu den wirksamsten Therapien gehört, kann die PRRT die NET nur stabilisieren, aber nicht heilen. Eine Verbesserung der PRRT ist daher notwendig.

Radioaktives Terbium-161 (161Tb) hat eine ähnliche Zerfallshalbwertszeit wie radioaktives Luthetium-177 (177Lu), gibt aber zusätzlich große Mengen an biologisch höchst wirksamer Strahlung ab, die nur eine sehr geringe Reichweite im Gewebe aufweist (bis zu einem tausendstel Millimeter).

Wir erwarten, dass die PRRT durch Verwendung von 161Tb-DOTA-LM3 im Vergleich zur Standardtherapie mit 177Lu-DOTATOC und 177Lu-DOTATATE mehrere Vorteile aufweist: 1) 161Tb-DOTA-LM3 bindet an viel mehr Rezeptor-Bindungsstellen und reichert sich hauptsächlich an der Tumorzellmembran an. 2) Die sehr starke aber kurz reichende Strahlung von 161Tb führt zu einer hohen therapeutischen Wirksamkeit vor allem an der Zellmembran, die strahlenempfindlicher ist als der restliche Zellinhalt. Dies führt zu einer 3 – 4-fach höheren Strahlendosis in der einzelnen Krebszelle.

In dieser Studie werden 161Tb-DOTA-LM3 und 177Lu-DOTATOC in 18 - 23 Patienten mit metastasiertem NET miteinander hinsichtlich der Tumor- und Organdosis sowie Therapieeffizienz verglichen. Wir erwarten mit 161Tb-DOTA-LM3 eine deutlich bessere Therapieeffizienz insbesondere für die Therapie von Mikrometastasen sowie von Tumoren mit geringer SST2-Expression.

Direct link to Lay Summary Last update: 27.09.2021

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Abstract

1. Summary of the research plan - rationale of the project: Neuroendocrine neoplasms (NENs) are a group of neoplasms with an increasing prevalence commonly located in the intestine, pancreas and lung. Less than 50% of NEN patients benefit from curative surgery as up to 50% of NENs are metastatic at diagnosis. The overexpression of somatostatin receptor subtype 2 (SST2), is a characteristic of NENs and presents an important molecular target for the management of these tumours. Peptide receptor radionuclide therapy (PRRT) targets the SST2 through the administration of radiolabelled SST2 agonists such as 177Lu-DOTATOC and 177Lu-DOTATATE. Although PRRT is one of the most efficient treatments for the management of NENs, it does only stabilize but not cure the disease. There is, thus, an unmet need to improve PRRT with more effective radiopharmaceuticals.Based on our recent preclinical studies, there is compelling evidence that terbium-161 (161Tb) is more powerful than lutetium (177Lu) not only in combination with SST2 agonists but particularly also with SST2 antagonists. 161Tb, has a similar half-life and ߯-radiation energy as 177Lu but in addition also emits high quantities of conversion- and Auger electrons (CE/AE, herein referred as AE). We therefore, propose to improve PRRT by using a potent SST2 antagonist (DOTA-LM3) labelled with 161Tb since 161Tb-DOTA-LM3 has several advantages compared to 177Lu-DOTATOC and 177Lu-DOTATATE: 1) SST2 antagonists target many more SST2 binding sites and accumulate mainly at the cellular membrane. 2) The AE of 161Tb deposit their energy over a short distance (1-1000 nm) resulting in a high relative biological effectiveness mainly to the cell membrane which seems to be more radiosensitive than the cytoplasm. 161Tb-DOTA-LM3 does, therefore, not only damage larger metastases by ß--radiation, but also leads to a 3-4 fold increased absorbed dose to single cancer cells Research question + specific aims: Does 161Tb-DOTA-LM3 outperform 177Lu-DOTATOC for PRRT in terms of 1) tumour/organ dosimetry results, 2) best objective response rate and 3) 12 months’ progression free survival (PFS)? The primary endpoints are the estimation of tumour-, bone marrow- and kidney doses for 177Lu-DOTATOC and 161Tb-DOTA-LM3 in the same patients (phase 0 study) and determination of the maximum tolerated dose of 3 cycles 161Tb-DOTA-LM3 (phase I study) which is crucial for planning future phase II/III studies.Experimental design + methods: Our project consists of a first-in-human/proof-of-concept study (phase 0 study) and a connected phase I study. The phase 0 study is a single centre, open label, prospective study to compare the dosimetry of 161Tb-DOTA-LM3 and 177Lu-DOTATOC in the same patients using a randomized cross-over design. Tumour- and organ dosimetry will be determined. The phase I part of the study is a single centre, open label, dose-finding study using the 3+3 design. To enable this study, the 161Tb production will be scaled-up and the 161Tb-DOTA-LM3 production will be optimized.Expected results and their value: 161Tb-DOTA-LM3 might improve PRRT by improved targeting of micro metastases in patients with SST2-positive NENs and possibly other tumours with relatively low SST2 expression such as pheochromocytoma, medullary thyroid cancer, small cell lung cancer and paraganglioma which might be the target for future projects. The study has the potential for a paradigm shift from standard PRRT with ß--radiation to combined ß--radiation and AE therapy using SST2 antagonists. In the future combined ß--radiation and AE therapy with antagonists could successfully expand PRRT to other receptor targeting systems such as bombesin receptors in prostate cancer, cholecystokinin-2 receptors in medullary thyroid cancer etc.
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