177Lutetium-octreotate Treatment Prediction Using Multimodality Imaging in Refractory NETs (LUMEN)

The LuMEn Study: 177Lu-octreotate Treatment Outcome Prediction Using Multimodality Imaging in Refractory Neuroendocrine Tumours.

The purpose of this study is to determine if 68Gallium-octreotate and 18Fluorodesoxyglucose uptake, apparent diffusion coefficient and post 177Lu-octreotate SPECT/CT dosimetry are reliable predictors for lesion-by-lesion treatment outcome.

Study Overview

• Status: Completed
• Conditions: Gastroenteropancreatic Neuroendocrine Tumors
• Intervention / Treatment: Drug: Intravenous injection of 177Lu-octreotate

Detailed Description

This is a feasibility study evaluating the use of 177Lutetium-octreotate in the treatment of advanced refractory Neuroendocrine Tumors.

Objectives of the study:

1. Primary (on a lesion basis): To assess the value of the following parameters (obtained through functional and molecular imaging) for predicting the lesion-by-lesion PRRT treatment outcome:

   • 18FDG uptake on 18FDG PET/CT
   • 68Ga-octreotate uptake on 68Ga-octreotate PET/CT
   • Apparent diffusion coefficient on diffusion weighted MRI (for these 3 parameters, absolute values at baseline)
   • Tumor dosimetry on post 177Lu-octreotate SPECT/CT after each cycle.
2. Secondary (on a patient basis): To generate a patient-based response model based on the previously defined parameters.

3. Exploratory (on a lesion basis): To assess the value of the parameters mentioned in the primary objective for predicting the lesion-by-lesion PRRT treatment outcome:

   • absolute values of the three imaging parameters and their relative changes after each cycle;
   • serial tumor dosimetry on post-177Lu-octreotate SPECT/CT after each cycle.

Treatment will consist of 177Lu-octreotate injections in fixed activities of 7,4 GigaBecqurel each, given 11-13 weeks apart, injected intravenously with simultaneous infusion of an amino acid solution. (Before amino acid nephroprotection, ondansetron, methylprednisolone and metoclopramid, are given intravenously in order to prevent nausea or vomiting). Approximately 30 min after the beginning of the amino acid solution, 177Lu-octreotate is co-infused over 15-30 minutes. The amino acid infusion is continued at the same rate for 3-5 more hours (total infusion lasts 4-6 hours).

In total, 4 cycles (= injections of 177Lu-octreotate) are planned. However, the total number of administered cycles will be limited by critical organ (kidneys and bone marrow) threshold toxicities.

Treatment efficacy will be assessed:

• on a lesion-basis (change of longest transversal diameter).
• on a patient-basis using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, B-1000
    • Jules Bordet Institute

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:

Patient-based:

1. Age above or equal to 18 years.
2. Histology-proven advanced GEP-NETs.

3. Disease progression defined as follows (at least one of the following):

   - Radiological disease progression (according to RECIST 1.1) on an MRI or CT over the last 12 months Or

   - Disease progression on a somatostatin receptor-imaging, PET/CT or SPECT/CT over the last 12 months [apparition of new lesion(s) or increase in the transaxial plane diameter of more than 30% on the same imaging modality] Or

   - Both of the following criteria (a+b):

   1. clinical progression:

      • sustained (for more than 2 weeks) increase of NET-specific hormonal hypersecretion related symptom frequency by 50% or,
      • sustained (for more than 2 weeks) increase of severity by 1 grade (according to NCI-CTCAE version 4.03).
   2. biochemical progression: by increase of NET-specific tumor markers (plasma Chromogranin A, plasma NSE, urine 5-HIAA or other) in two successive measurements.
4. Disease refractory to SSA's and/or standard systemic therapy available in Belgium at the time of inclusion criteria.
5. Long-acting SSAs should be discontinued at least 4 weeks before study treatment start date and, if needed, switched to short-acting analogues which should be stopped 48h before the treatment date.
6. Adequate renal function with GFR ≥ 50 mL/min/1.73m2 (evaluated by 51Cr-EDTA test).
7. Adequate bone marrow function with hemoglobin ≥ 9 g/dL; neutrophil ≥ 1.5·103/μL; platelet count ≥ 100·103/μL.
8. Adequate liver function with total bilirubin ≤ 2 x ULN and transaminases ≤ 5 x ULN, serum albumin > 3 g/dL with normal prothrombin time (> 70%).
9. ECOG Performance Status ≤ 1.
10. Women of childbearing potential and men with partners of childbearing potential must agree to use a highly-effective form of contraception for the duration of study participation and up to six months after the end of the treatment. A pregnancy test (serum) must be performed within 4 weeks prior to inclusion for every female patient of childbearing potential and it must be negative.
11. Patient's written informed consent obtained prior to any study procedure.

12. All necessary baseline procedures should be performed within 4 weeks prior to first 177Lu-octreotate injection (D0).

    Lesion-based:

13. The patient must have at least one target lesion fulfilling all of the below criteria:

    • On the 68Ga-octreotate PET/CT: tumor uptake higher than the physiological liver uptake (grade III or IV of the Rotterdam visual score) in a lesion with longest transaxial plane diameter ≥20mm (measured on the CT, part of the PET/CT);
    • At least one of these lesions morphologically measurable according to RECIST 1.1 and progressive on the MRI (or CT if MRI is not applicable);
    • Target lesion should not have been previously irradiated.

Exclusion Criteria:

1. Resectable tumor with curative intent.
2. Any major surgery within the last 6 weeks prior to inclusion in the study
3. Radiotherapy, chemotherapy, embolization, mammalian target of rapamycin (mTOR)-inhibitors, receptor tyrosine-kinase inhibitors, interferon, or other investigational therapy within the last 12 weeks prior to inclusion in the study.
4. Diffuse bone marrow infiltration on the baseline 68Ga-octreotate PET/CT confirmed by MRI.
5. Prior external beam radiotherapy on kidneys or on more than 25% of bone marrow.
6. Patients with known uncontrolled brain metastases.
7. Patients with a significant medical, neuro-psychiatric, or surgical condition, currently uncontrolled by treatment, which, in the investigator's opinion, may interfere with completion of the study.
8. Pregnant or lactating patients.
9. Women of childbearing potential and men with partners of child-bearing potential refusing an adequate contraception.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
OTHER: 177Lu-octreotate therapy; Treatment will consist of 177Lu-octreotate injections in fixed activities of 7,4 GBq (200 mCi) (±5%) each, given 12 weeks (±1 week) apart, injected intravenously simultaneously with nephroprotective perfusion of an amino acid solution.	Drug: Intravenous injection of 177Lu-octreotate; Treatment will consist of 177Lu-octreotate injections in fixed activities of 7,4 GBq (200 mCi) (±5%) each, given 12 weeks (±1 week) apart, injected intravenously simultaneously with nephroprotective perfusion of an amino acid solution.; Other Names: 177Lu-DOTATATE; Lutate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The time to progression (TTP) for each target lesion assessed on MRI (or on CT scan if MRI is not possible).	TTP is defined as the time between treatment initiation and objective tumor progression with censoring of patients who die as a result of any cause.	4 years [Anticipated]

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best morphological response according to RECIST 1.1		4 years [Anticipated]
Progression Free Survival	PFS is defined as the time between treatment initiation and the first of the following events: disease progression (clinical or radiological) or death resulting from any cause.	4 years [Anticipated]
Biochemical response (evolution of NET-specific tumoral uptake).		4 years [Anticipated]

Other Outcome Measures

Outcome Measure	Time Frame
The time to progression (TTP) for each target lesion assessed on MRI (or on CT scan if MRI is not applicable).	4 years [Anticipated]

Collaborators and Investigators

• Sponsor: Jules Bordet Institute
• Investigators: Study Chair: Patrick Flamen, M.D., Ph.D., Jules Bordet Institute; Principal Investigator: Amélie Deleporte, MD, Jules Bordet Institute; Study Chair: Ioannis Karfis, MD, Jules Bordet Institute

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (ACTUAL): January 14, 2022
• Study Completion (ACTUAL): September 19, 2022

Study Registration Dates

• First Submitted: April 25, 2013
• First Submitted That Met QC Criteria: April 25, 2013
• First Posted (ESTIMATE): April 29, 2013

Study Record Updates

• Last Update Posted (ACTUAL): November 10, 2022
• Last Update Submitted That Met QC Criteria: November 7, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Neuroendocrine Tumors; Peptide Receptor Radionuclide Therapy (PRRT)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Molecular Mechanisms of Pharmacological Action; Radiopharmaceuticals; Lutetium Lu 177 dotatate
• Other Study ID Numbers: IJBMNLUMEN; 2012-003666-41 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO