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

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

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.

Study Overview

• Status: Completed
• Conditions: Thyroid Cancer, Medullary
• Intervention / Treatment: Drug: 177Lu-PP-F11N; Drug: Sacuitril

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • University Hospital Basel, Clinic for radiology and nuclear medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Collaborators: University Hospital, Zürich; University Hospital Freiburg; Krebsforschung Schweiz, Bern, Switzerland; Center for Proton Therapy, Paul Scherrer Institute, Villigen,Switzerland
• Investigators: Principal Investigator: Christof Rottenburger, Dr. med., University Hospital Basel, Clinic for radiology and nuclear medicine; Study Director: Damian Wild, PhD Dr, University Hospital Basel, Clinic for radiology and nuclear medicine

Publications and helpful links

General Publications

• 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.

Helpful Links

• University Hospital Basel Homepage

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2018
• Primary Completion (Actual): December 14, 2021
• Study Completion (Actual): December 14, 2021

Study Registration Dates

• First Submitted: August 20, 2018
• First Submitted That Met QC Criteria: August 22, 2018
• First Posted (Actual): August 27, 2018

Study Record Updates

• Last Update Posted (Actual): February 10, 2022
• Last Update Submitted That Met QC Criteria: February 9, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Calcitonin; Gastrin; Medullary thyroid carcinoma; Peptide receptor radionuclide therapy; Cholecystokinin-2 receptor
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Endocrine System Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Thyroid Diseases; Thyroid Neoplasms; Molecular Mechanisms of Pharmacological Action; Angiotensin Receptor Antagonists; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: 2018-00972

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No