177Lu-PP-F11N in Combination With Sacubitril for Receptor Targeted Therapy and Imaging of Metastatic Thyroid Cancer

A phase 0 study (Lumed study part A) was already performed, showing low toxicity of 177Lu-PP-F11N and tumor uptake in all patients. Co-injection of Physiogel (Gelofusin) showed insignificant reduction of kidney uptake and can therefore be omitted for a radionuclide therapy with 177Lu-PP-F11N. In this study, the effect of the NEP-1 inhibitor Sacuitril on the in-vivo stability of 177Lu-PP-F11N and the uptake, respectively radiation doses in MTC metastases and organs will be evaluated, using a cross-over design already used for the Lumed part A study. Each patient will receive two injections of 177Lu-PP-F11N, with and without additional medication with Sacuitril Imaging findings, acquired by SPECT/CT, will be compared to imaging with 68Ga-DOTATOC positron emission tomography (PET)/CT. The inclusion of 8 patients is planned.

• 177Lu-PP-F11N (Drug), also known as Radiopharmakon: Intravenous application of 2 x 1 gigabequerel (GBq) 177Lu-PP-F11N with and without co-medication with Sacuitril (100 mg Entresto) in each patient
• Sacuitril (Drug), also known as Entresto: Medication with Sacuitril (100 mg Entresto) additional to the injection of 177Lu-PP-F11N

Primary outcomes

• Tumor radiation doses [Measurement up to 72 hours after each injection of 177Lu-PP-F11N]: Evaluation of the radiation doses in tumor tissue from MTC after injection of 177Lu-PP-F11N alone and in combination with Sacuitril (Entresto)

Secondary outcomes

• Kidney radiation doses [Measurement up to 72 hours after each injection of 177Lu-PP-F11N]: Evaluation of the radiation doses in the kidneys and the tumor-to-kidney dose ratios after injection of 177Lu-PP-F11N alone and in combination with Sacuitril (Entresto)
• Organ radiation doses [Measurement up to 72 hours after each injection of 177Lu-PP-F11N]: Evaluation of the radiation doses in other organs and the appropriate organ-to-kidney dose ratios after injection of 177Lu-PP-F11N alone and in combination with Sacuitril (Entresto)
• In-vivo stability [Blood samples for measurement 5 and 30 minutes post injection of 177Lu-PP-F11N]: Measurement (HPLC) of the in-vivo stability of 177Lu-PP-F11N alone and in combination with Sacuitril (Entresto).
• Autoradiography [Through study completion, up to 18 months]: In case of surgery with available tumor tissue samples, imaging results will be compared with autoradiographic analysis of somatostatine- and CCK2-receptor expression in tumor tissue.

Other outcomes

• Chromogranin A [Measurement up to 72 hours after the first injection of 177Lu-PP-F11N]: Chromogranin A blood values will be compared to the radiation doses of the stomach.
• 68Ga-DOTATOC PET/CT [Measurement up to 72 hours after each injection of 177Lu-PP-F11N]: Comparison of tumor imaging by 68Ga-DOTATOC PET/CT and 177Lu-PP-F11N SPECT/CT

Sex: All, ages: 18 Years to 64 Years

Inclusion Criteria:

* Advanced MTC with elevated levels of calcitonin (> 100 pg/ml) and/or calcitonin-doubling time < 24 months before or after total thyroidectomy
* 68Ga-DOTATOC PET/CT not older than 12 weeks
* Age > 18 years
* Informed consent

Exclusion Criteria:

* Medication with Vandetanib 3 weeks before the study and during the study
* Renal failure (calculated glomerular filtration rate (GFR) < 60 ml/min per 1.73 m2 body surface).
* Bone marrow failure (thrombocytes < 70 000/μl, leucocytes < 2 500/μl, hemoglobin < 8 g/dl).
* Pregnancy and breast feeding
* Known, serious side reaction in the case of a former application of pentagastrin
* Active, second malignancy oder remission after second malignancy < 5 years
* Age over 64 years
* Systolic bood pressure < 112 mmHg at the time of screening
* Simultaneous medication with angiotensin converting enzyme (ACE)-inhibitors, or withdrawal for less than 36 h prior to the medication with Entresto or simultaneous medication with AT-II-receptor blockers
* Known intolerance to Sacubitril or Valsartan
* Known angioedema in anamnesis in the context of a medication with an ACE-inhibitor or an AT-II-receptor blocker

• Results publication: Sauter AW, Mansi R, Hassiepen U, Muller L, Panigada T, Wiehr S, Wild AM, Geistlich S, Behe M, Rottenburger C, Wild D, Fani M. Targeting of the Cholecystokinin-2 Receptor with the Minigastrin Analog 177Lu-DOTA-PP-F11N: Does the Use of Protease Inhibitors Further Improve In Vivo Distribution? J Nucl Med. 2019 Mar;60(3):393-399. doi: 10.2967/jnumed.118.207845. Epub 2018 Jul 12. PMID 30002107
• Results publication: Rottenburger C, Hentschel M, Furstner M, McDougall L, Kottoros D, Kaul F, Mansi R, Fani M, Vija AH, Schibli R, Geistlich S, Behe M, Christ ER, Wild D. In-vivo inhibition of neutral endopeptidase 1 results in higher absorbed tumor doses of [177Lu]Lu-PP-F11N in humans: the lumed phase 0b study. EJNMMI Res. 2024 Apr 6;14(1):37. doi: 10.1186/s13550-024-01101-w. PMID 38581480

• Christof Rottenburger, Dr. med., Principal investigator, University Hospital Basel, Clinic for radiology and nuclear medicine
• Damian Wild, PhD Dr, Study director, University Hospital Basel, Clinic for radiology and nuclear medicine

NIH grants: 2018