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

Study Overview
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Brief Summary
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The purpose of this study is to determine the use of 177Lu-PP-F11N for imaging and therapy of patients with advanced medullary thyroid carcinoma (MTC). 177Lu-PP-F11N is a gastrin analogon, binding to cholecystokinin-2 receptors. This receptors show an overexpression on more than 90 % of medullary thyroid carcinomas.

Detailed Description
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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.

Official Title
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177Lu-PP-F11N in Combination With Sacubitril for Receptor Targeted Therapy and Imaging of Metastatic Thyroid Cancer (Lumed Phase 0/B)

Conditions
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Thyroid Cancer, Medullary

Intervention / Treatment
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* Drug: 177Lu-PP-F11N
* Drug: Sacuitril


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Group 1 patients will receive first 177Lu-PP-F11N alone, second 177Lu-PP-F11N in combination with Sacuitril. Group 2 patients will first receive 177Lu-PP-F11N in combination with Sacuitril, second 177Lu-PP-F11N alone. Affiliation of patients to Groups 1 and 2 will be randomised.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Entresto second<br>First intravenous application of 2 x 1 gigabequerel (GBq) 177Lu-PP-F11N without and second injection with additional medication of Sacuitril (100 mg Entresto)(crossover) | Drug: 177Lu-PP-F11N<br>* Intravenous application of 2 x 1 gigabequerel (GBq) 177Lu-PP-F11N with and without co-medication with Sacuitril (100 mg Entresto) in each patient<br>* Other names: Radiopharmakon;Drug: Sacuitril<br>* Medication with Sacuitril (100 mg Entresto) additional to the injection of 177Lu-PP-F11N<br>* Other names: Entresto;|
| Experimental: Entresto first<br>First intravenous application of 2 x 1 gigabequerel (GBq) 177Lu-PP-F11N with and second injection without additional medication of Sacuitril (100 mg Entresto)(crossover) | Drug: 177Lu-PP-F11N<br>* Intravenous application of 2 x 1 gigabequerel (GBq) 177Lu-PP-F11N with and without co-medication with Sacuitril (100 mg Entresto) in each patient<br>* Other names: Radiopharmakon;Drug: Sacuitril<br>* Medication with Sacuitril (100 mg Entresto) additional to the injection of 177Lu-PP-F11N<br>* Other names: Entresto;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor radiation doses | Evaluation of the radiation doses in tumor tissue from MTC after injection of 177Lu-PP-F11N alone and in combination with Sacuitril (Entresto) | Measurement up to 72 hours after each injection of 177Lu-PP-F11N | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kidney radiation doses | 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) | Measurement up to 72 hours after each injection of 177Lu-PP-F11N | 
| Organ radiation doses | 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) | Measurement up to 72 hours after each injection of 177Lu-PP-F11N | 
| In-vivo stability | Measurement (HPLC) of the in-vivo stability of 177Lu-PP-F11N alone and in combination with Sacuitril (Entresto). | Blood samples for measurement 5 and 30 minutes post injection of 177Lu-PP-F11N | 
| Autoradiography | 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. | Through study completion, up to 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Calcitonin, Medullary thyroid carcinoma, Peptide receptor radionuclide therapy, Gastrin, Cholecystokinin-2 receptor