Intra-arterial Hepatic (IAH) Infusion of Radiolabelled Somatostatin Analogs in GEP-NET Patients With Dominant Liver Metastases (LUTARTERIAL)

"Imaging With 68Ga-DOTA-peptides and Peptide Receptor Radionuclide Therapy With 177Lu-DOTA-peptides of Gastroenteropancreatic Neuroendocrine Tumors: Interest of Intra-arterial Hepatic Infusion in Patients With Dominant Liver Metastases"

The management of liver metastases in neuroendocrine neoplasms is challenging. Peptide receptor radionuclide therapy with radiolabeled somatostatin analogs (SSA) is one of the most promising therapeutic options. As liver is the most frequent site of metastatic disease, our project proposes to compare administration of radiolabeled SSA by arterial intrahepatic infusion (experimental approach) vs intravenous administration (conventional). Evaluation will be made by (i) comparing 68Ga-DOTA-peptides uptake after intra-hepatic versus intravenous route (imaging), (ii) by evaluating the safety of an additional intra-hepatic administration of therapeutic radiolabeled SSA (therapy).

Study Overview

• Status: Recruiting
• Conditions: Neuroendocrine Tumor; Liver Metastases; Neuroendocrine Gastroenteropancreatic Tumour
• Intervention / Treatment: Procedure: Positron emission tomography computed tomography (PET/CT) with Intra-hepatic (IAH) injection; Procedure: Positron emission tomography computed tomography (PET/CT) with Intravenous (IV) injection; Drug: LUTATHERA® by intra-arterial hepatic (IAH) injection; Procedure: Scan

Detailed Description

Liver metastases of neuroendocrine tumors of gastro-entero-pancreatic origin are one of the most limiting factors of patient survival. Peptide receptor radionuclide therapy with radiolabeled somatostatin analogs (SSA) such as LUTATHERA® represents now a major therapeutic option. As far as these metastases are mainly perfused by the hepatic artery, it could be relevant to deliver the treatment by intra-hepatic route, in order to achieve a maximized dose to the tumour when compared with a systemic conventional administration, while also reducing kidney and bone marrow toxicity. By using radiolabeled SSA for imaging and therapy, the present project aims to compare the uptake of 68Ga-DOTA-peptides after intra-hepatic versus intravenous injections for targeted liver metastases, as well as for dose limiting organs (kidney, spleen, healthy liver, bone marrow) and extra-hepatic lesions if present. The investigators will also evaluate whether the intra-hepatic infusion of one treatment dose of LUTATHERA® after conventional treatment by 4 intravenous administrations, is safe.

Following 4 intravenous administrations of LUTATHERA® in GEP-NET with dominant liver metastases, patients who gave informed consent will be enrolled for 2 PET-scans, the first one after intra-hepatic injection of 68Ga-DOTA-peptides and the second one after intravenous injection for purpose of uptake comparison by 5 liver metastases chosen by radiologists on MRI.

In 10 patients who meet a predefined enhancement ratio of 3, a 5th dose of LUTATHERA® will be administered by intra-arterial hepatic injection. An average enhancement ratio of 3.75 is expected from intra-arterial injection compared to intravenous results. Those 10 patients will be evaluated for 177Lu-DOTA-peptide activity and residence time by SPECT/CT imaging.

Follow-up through 18 months will include clinical examination, MRI and CT scan, as usually performed in these clinical settings and progression

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ghoufrane TLILI, Dr; Phone Number: 05 57 65 64 08; Email: ghoufrane.tlili@chu-bordeaux.fr
• Study Contact Backup: Name: Macary Guillaume; Phone Number: 05 57 62 32 52; Email: guillaume.macary@chu-bordeaux.fr

Study Locations

• France
  • Bordeaux, France, 33000
    • Not yet recruiting
    • Institut Bergonié
    • Contact: Yann GODBERT, Dr; Email: y.godbert@bordeaux.unicancer.fr
  • Nîmes, France, 30029
    • Not yet recruiting
    • Institut de cancérologie du Gard (ICG) - CHU de Nîmes
    • Contact: Vincent BOUDOUSQ, Dr; Email: vincent.boudousq@chu-nimes.fr
  • Pessac, France, 33604
    • Recruiting
    • CHU Bordeaux - Hôpital Haut Lévêque
    • Contact: Ghoufrane TLILI, Dr; Phone Number: 05 57 65 64 08; Email: ghoufrane.tlili@chu-bordeaux.fr
    • Contact: Guillaume Macary; Phone Number: 05 57 62 32 52; Email: guillaume.macary@chu-bordeaux.fr
    • Principal Investigator: Ghoufrane TLILI
  • Toulouse, France, 31100
    • Not yet recruiting
    • Institut Universitaire du Cancer de Toulouse (IUCT) Oncopole
    • Contact: Frederic Courbon, Pr; Email: courbon.frederic@iuct-oncopole.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically proven well differentiated neuroendocrine tumor (NET) of gastrointestinal or pancreatic origin (GEP).
• Patients are progressive after treatment with cold somatostatin analog (within 12 months according to RECIST), or as soon as the diagnosis is made in case of hepatic invasion > 50% without waiting for tumour progression
• Patient has received 4 standard of care LUTATHERA® cycles
• Liver Metastatic disease dominant or exclusive and assessable by RECIST 1.1, and not amenable to surgical resection after the last cycle
• ECOG performance status 0-2
• Adequate kidney and liver function: creatinine clearance ≥ 50 mL/min, ALT/AST ≤ 2,5x the upper limit of normal
• With no evidence of hematologic alteration after 4 LUTATHERA® cycles: hemoglobin ≥ 8 g/dL, neutrophils ≥ 1500/ mm3, platelets ≥ 100.000/mm3
• Age ≥ 18 years, no superior limit
• Contraception required in pre-menopausal female (Intrauterine device, Progestin Pills, Combined Oral Contraceptives, Monthly Injectables, Progestin Injectables, Combined Patch, Combined Vaginal Ring, Female Sterilization, Vasectomy, Implants) and men for at least 6 months after the last LUTATHERA ® injection.
• Patient´s signed written informed consent
• Patient affiliated to a social security system

Exclusion Criteria:

• Patients with complete response defined by the absence of lesion according to RECIST 1.1 realized during morphological imaging at inclusion (chest-abdomen-pelvis CT scan and hepatic MRI)
• No residual uptake according to standard 177-Lu scintigraphy performed in the clinical routine 24 hours after each LUTATHERA IV treatment
• Carcinoid heart disease (LVEF < 40%)
• Dominant or threatening extrahepatic metastases or that may affect vital prognosis
• Contraindications to intra-hepatic arterial infusion (coagulation disorders, portal thrombosis, intra-hepatic biliary tract dilatation, digestive or biliary anastomosis or fistula, cirrhosis (Child Pugh B8 or C…)
• Serum albumin <30 g/L unless prothrombin time is within the normal range.
• Heart failure, myocardial infarction, stroke, uncontrolled arterial hypertension under optimal treatment (≥ 160/95 mmHg), pulmonary embolism or revascularization procedure, unstable angina pectoris, uncontrolled cardiac arrhythmia, and clinically significant bradycardia during the last 12 months.
• Individuals under legal protection or unable of giving their informed consent
• Pregnancy or breast feeding
• Currently participating to another clinical research protocol
• Individuals under legal protection or unable of giving their informed consent
• MRI scan contraindicated
• LUTATHERA® contraindicated or toxicity during one of the IV administrations leading to a reduction or cancellation of the following dose

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 68Ga-DOTA-peptides PET/CT; 68Ga-DOTA-peptides injections for targeted liver metastases in Positron emission tomography-computed tomography (PET/CT)	Procedure: Positron emission tomography computed tomography (PET/CT) with Intra-hepatic (IAH) injection; Intra-hepatic injection of 68Ga-DOTA-peptides for targeted liver metastases in Positron emission tomography-computed tomography (PET/CT); Procedure: Positron emission tomography computed tomography (PET/CT) with Intravenous (IV) injection; intravenous injection of 68Ga-DOTA-peptides for targeted liver metastases in Positron emission tomography-computed tomography (PET/CT)
EXPERIMENTAL: LUTATHERA® by intra-arterial hepatic injection (IAH); One treatment dose of LUTATHERA® by intra-arterial hepatic injection after conventional treatment by 4 intravenous administrations	Procedure: Positron emission tomography computed tomography (PET/CT) with Intra-hepatic (IAH) injection; Intra-hepatic injection of 68Ga-DOTA-peptides for targeted liver metastases in Positron emission tomography-computed tomography (PET/CT); Procedure: Positron emission tomography computed tomography (PET/CT) with Intravenous (IV) injection; intravenous injection of 68Ga-DOTA-peptides for targeted liver metastases in Positron emission tomography-computed tomography (PET/CT); Drug: LUTATHERA® by intra-arterial hepatic (IAH) injection; One treatment dose of LUTATHERA® by IAH injection for the 10 first patients with an PET/CT ratio greater then 3. The LUTATHERA® by intra-arterial hepatic injection treatment is realised after the conventional treatment by 4 intravenous administrations; Procedure: Scan; Scans after completion of LUTATHERA® treatment injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Standardized uptake value (SUVmax) on liver metastases	Standardized uptake value (SUVmax) on liver metastase obtained on PET/CT imaging after injection of 68Ga-DOTA-peptides	Day 0 (First PET/CT)
Standardized uptake value (SUVmax) on liver metastases	Standardized uptake value (SUVmax) on liver metastase obtained on PET/CT imaging after injection of 68Ga-DOTA-peptides	Day 3 (second PET/CT)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Standardized uptake value (SUVmax) on healthy liver	Standardized uptake value (SUVmax) on healthy liver obtained on PET/CT imaging after injection of 68Ga-DOTA-peptides	Day 0 (First PET/CT)
Standardized uptake value (SUVmax) on healthy liver	Standardized uptake value (SUVmax) on healthy liver obtained on PET/CT imaging after injection of 68Ga-DOTA-peptides	Day 3 (second PET/CT)
Standardized uptake value (SUVmax) on kidneys	Standardized uptake value (SUVmax) on kidneys obtained on PET/CT imaging after injection of 68Ga-DOTA-peptides	Day 0 (First PET/CT)
Standardized uptake value (SUVmax) on kidneys	Standardized uptake value (SUVmax) on kidneys obtained on PET/CT imaging after injection of 68Ga-DOTA-peptides	Day 3 (second PET/CT)
Standardized uptake value (SUVmax) on bone marrow	Standardized uptake value (SUVmax) on bone marrow obtained on PET/CT imaging after injection of 68Ga-DOTA-peptides	Day 0 (First PET/CT)
Standardized uptake value (SUVmax) on bone marrow	Standardized uptake value (SUVmax) on bone marrow obtained on PET/CT imaging after injection of 68Ga-DOTA-peptides	Day 3 (second PET/CT)
Standardized uptake value (SUVmax) on spleen	Standardized uptake value (SUVmax) on spleen obtained on PET/CT imaging after injection of 68Ga-DOTA-peptides	Day 0 (First PET/CT)
Standardized uptake value (SUVmax) on spleen	Standardized uptake value (SUVmax) on spleen obtained on PET/CT imaging after injection of 68Ga-DOTA-peptides	Day 3 (second PET/CT)
Standardized uptake value (SUVmax) on associated extra-hepatic metastases	Standardized uptake value (SUVmax) on associated extra-hepatic metastases obtained on PET/CT imaging after injection of 68Ga-DOTA-peptides	Day 0 (First PET/CT)
Standardized uptake value (SUVmax) on associated extra-hepatic metastases	Standardized uptake value (SUVmax) on associated extra-hepatic metastases obtained on PET/CT imaging after injection of 68Ga-DOTA-peptides	Day 3 (second PET/CT)
177Lu-DOTA-peptide dosimetry	Absorbed dose in different tissue of the 5 hepatic targets, possible extra-hepatic lesions and healthy organs (healthy liver, kidney, bone marrow, spleen)	Day 18

Collaborators and Investigators

• Sponsor: University Hospital, Bordeaux
• Collaborators: Advanced Accelerator Applications
• Investigators: Principal Investigator: Ghoufrane TLILI, University Hospital, Bordeaux

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 24, 2021
• Primary Completion (ANTICIPATED): March 24, 2023
• Study Completion (ANTICIPATED): September 24, 2024

Study Registration Dates

• First Submitted: April 6, 2021
• First Submitted That Met QC Criteria: April 7, 2021
• First Posted (ACTUAL): April 8, 2021

Study Record Updates

• Last Update Posted (ACTUAL): December 1, 2021
• Last Update Submitted That Met QC Criteria: November 18, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Neuroendocrine tumour; Liver Metastases; Peptide Receptor Radionuclide Therapy; Neuroendocrine gastroenteropancreatic (GEP) tumour; 68Ga- DOTA-peptides PET CT; 177Lutetium-Octreotate
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms by Site; Digestive System Neoplasms; Liver Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neoplastic Processes; Neoplasms; Neoplasm Metastasis; Liver Neoplasms; Neuroendocrine Tumors; Molecular Mechanisms of Pharmacological Action; Radiopharmaceuticals; Lutetium Lu 177 dotatate
• Other Study ID Numbers: CHUBX 2017/47

Drug and device information, study documents

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