Peptide Receptor Radionuclide Therapy (PRRT) in Tumors With High Expression of Somatostatin Receptors (Phase 2) (FENET-2016)

Peptide Receptor Radionuclide Therapy (PRRT) in Tumors With High Expression of Somatostatin Receptors

The rationale behind the purpose of this study lays on:

• the evidence that PRRT could represent a valuable treatment for the majority of patients with neuroendocrine tumor (NET) in disease progression, operated or inoperable, presenting lesions expressing somatostatin receptors and for which standard treatments are not already available;
• the current impossibility of acquiring on the market radiolabelled analogues of somatostatin used for PRRT with marketing authorisation;
• the need to collect a larger case history than in previous studies;
• the need to stratify the various histotypes based on the response obtained;
• the need to define new treatment schemes that guarantee the maximum efficacy and the lowest possible toxicity - with low cumulative (and per cycle) activities radiopharmaceutical and according to the concept of dose hyperfractionation - with a view to an optimal balance between risk and benefit.

Study Overview

• Status: Recruiting
• Conditions: Neuroendocrine Tumors; Peptide Receptor Radionuclide Therapy (PRRT)
• Intervention / Treatment: Radiation: Lutetium-177 (177Lu)-DOTATOC; Radiation: Yttrium-90 (90Y)-DOTATOC; Radiation: 177Lu-DOTATOC + 90Y-DOTATOC; Radiation: Re-treatment 177Lu-DOTATOC; Radiation: Re-treatment 90Y-DOTATOC

• Study Type: Interventional
• Enrollment (Anticipated): 250
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mirco Bartolomei, MD; Phone Number: 0532236082; Email: m.bartolomei@ospfe.it
• Study Contact Backup: Name: Licia Uccelli, PhD; Phone Number: 0532237462; Email: licia.uccelli@unife.it

Study Locations

• Italy
  • Ferrara, Italy, 44124
    • Recruiting
    • University Hospital of Ferrara
    • Contact: Mirco Bartolomei, MD; Phone Number: 0532-236082; Email: m.bartolomei@ospfe.it
    • Contact: Phone Number: 0532-236387; Email: medicina.nucleare@ospfe.it

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:

• 1. Age ≥18 years, of both sexes, of any ethnicity;
• 2. Cyto-histological and immunohistochemical diagnosis of NET;
• 3. Evaluation of the cell proliferation index by studying Ki-67 and / or E3 ubiquitin-protein ligase (MIB-1).
• 4. Illness measurable according to RECIST 1.1 criteria by imaging conventional (CT with contrast medium or MRI with contrast medium) not earlier than two months with respect to enrollment;
• 5. Elevated expression of somatostatin receptors documented by PET-CT with 68Ga-DOTATOC in the target lesion (s). It is defined as "high expression of somatostatin receptors "a ratio of Maximum standardized uptake value (SUVmax) lesion / Mean standardized uptake value (SUVmean) muscle ≥ 4: 1 calculated with semi-quantitative analysis on examination PET-CT with 68Ga-DOTATOC;
• 6. Dosage of Chromogranin A (and any other specific markers) not prior to two months of enrollment;
• 7. Evaluation of glucose metabolism in the target lesion (s) by PET-CT with 18F-FDG;
• 8. Preserved haematological, hepatic and renal parameters, in particular: white blood cells ≥2500 / μL; platelets ≥ 90000 / μL; hemoglobin ≥ 9 gr / dL; creatinine ≤ 2 mg / dL; bilirubin ≤ 2.5 mg / dL
• 9. Eastern Cooperative Oncology Group (ECOG) performance status ≤2;
• 10. Life expectancy ≥ 6 months;
• 11. Stable or progressive disease, at any stage, both in operated patients that inoperable;
• 12. Absence of standard treatments already documented and of equal effectiveness;
• 13. Absence of surgical, chemotherapy and / or radiotherapy treatments for at least 30 days. On the other hand, patients in therapy with somatostatin analogues or biologics, such as mechanistic target of rapamycin (m-TOR) inhibitors;
• 14. Voluntary participation in the study by signing the consent form informed, after reading and complete understanding of the information notes.

Exclusion Criteria:

• 1. Lack of the requirements listed above;
• 2. State of pregnancy;
• 3. Breastfeeding and relative refusal to suspend breastfeeding;
• 4. Participation in another therapeutic experimental clinical protocol in the four weeks prior to the PRRT;
• 5. Bone marrow invasion of disease> 25% confirmed;
• 6. Previous extensive radiotherapy treatments.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Midgut NETs; 75 patients affected by non-functional and functional NETs arising from: stomach, duodenum, jejunum, ileum, colon and rectum.	Radiation: Lutetium-177 (177Lu)-DOTATOC; 5 cycles of 3,7 e 5,55 gigabequerel (GBq) of 177Lu-DOTATOC every 8-10 weeks. Cumulative activity: 18,5 e 27,75 GBq; Other Names: "MONO"; Radiation: Yttrium-90 (90Y)-DOTATOC; 5 cycles of 1,85 e 2,775 GBq of 90Y-DOTATOC every 8-10 weeks. Cumulative activity: 9,25 e 13,875 GBq; Radiation: 177Lu-DOTATOC + 90Y-DOTATOC; 3 cycles of 3,7 e 5,55 GBq of 177Lu-DOTATOC alternated with 2 cycles of 1,85 e 2,775 GBq of 90Y-DOTATOC every 8-10 weeks. Cumulative activity: 18,5 e 27,75 GBq of 177Lu-DOTATOC and 9,25 e 13,875 GBq of 90Y-DOTATOC; Other Names: "DUO"; Radiation: Re-treatment 177Lu-DOTATOC; 3 cycles of 3,7 e 5,55 GBq of 177Lu-DOTATOC every 8-10weeks. Cumulative activity: 11,1 e 16,65 GBq of 177Lu-DOTATOC; Radiation: Re-treatment 90Y-DOTATOC; 3 cycles of 1,85 e 2,775 GBq of 90Y-DOTATOC every 8-10 weeks Cumulative activity: 5,55 e 8,325 GBq of 90Y-DOTATOC
Experimental: Pancreatic NETs; 75 patients affected by non-functional and functional NETs arising from Pancreas.	Radiation: Lutetium-177 (177Lu)-DOTATOC; 5 cycles of 3,7 e 5,55 gigabequerel (GBq) of 177Lu-DOTATOC every 8-10 weeks. Cumulative activity: 18,5 e 27,75 GBq; Other Names: "MONO"; Radiation: Yttrium-90 (90Y)-DOTATOC; 5 cycles of 1,85 e 2,775 GBq of 90Y-DOTATOC every 8-10 weeks. Cumulative activity: 9,25 e 13,875 GBq; Radiation: 177Lu-DOTATOC + 90Y-DOTATOC; 3 cycles of 3,7 e 5,55 GBq of 177Lu-DOTATOC alternated with 2 cycles of 1,85 e 2,775 GBq of 90Y-DOTATOC every 8-10 weeks. Cumulative activity: 18,5 e 27,75 GBq of 177Lu-DOTATOC and 9,25 e 13,875 GBq of 90Y-DOTATOC; Other Names: "DUO"; Radiation: Re-treatment 177Lu-DOTATOC; 3 cycles of 3,7 e 5,55 GBq of 177Lu-DOTATOC every 8-10weeks. Cumulative activity: 11,1 e 16,65 GBq of 177Lu-DOTATOC; Radiation: Re-treatment 90Y-DOTATOC; 3 cycles of 1,85 e 2,775 GBq of 90Y-DOTATOC every 8-10 weeks Cumulative activity: 5,55 e 8,325 GBq of 90Y-DOTATOC
Experimental: Bronchial NETs; 25 patients affected by non-functional and functional Bronchial NETs.	Radiation: Lutetium-177 (177Lu)-DOTATOC; 5 cycles of 3,7 e 5,55 gigabequerel (GBq) of 177Lu-DOTATOC every 8-10 weeks. Cumulative activity: 18,5 e 27,75 GBq; Other Names: "MONO"; Radiation: Yttrium-90 (90Y)-DOTATOC; 5 cycles of 1,85 e 2,775 GBq of 90Y-DOTATOC every 8-10 weeks. Cumulative activity: 9,25 e 13,875 GBq; Radiation: 177Lu-DOTATOC + 90Y-DOTATOC; 3 cycles of 3,7 e 5,55 GBq of 177Lu-DOTATOC alternated with 2 cycles of 1,85 e 2,775 GBq of 90Y-DOTATOC every 8-10 weeks. Cumulative activity: 18,5 e 27,75 GBq of 177Lu-DOTATOC and 9,25 e 13,875 GBq of 90Y-DOTATOC; Other Names: "DUO"; Radiation: Re-treatment 177Lu-DOTATOC; 3 cycles of 3,7 e 5,55 GBq of 177Lu-DOTATOC every 8-10weeks. Cumulative activity: 11,1 e 16,65 GBq of 177Lu-DOTATOC; Radiation: Re-treatment 90Y-DOTATOC; 3 cycles of 1,85 e 2,775 GBq of 90Y-DOTATOC every 8-10 weeks Cumulative activity: 5,55 e 8,325 GBq of 90Y-DOTATOC
Experimental: Sympathetic-Adrenergic axis NEts; 25 patients affected by non-functional and functional: Pheochromocytoma, Paraganglioma and Neuroblastoma	Radiation: Lutetium-177 (177Lu)-DOTATOC; 5 cycles of 3,7 e 5,55 gigabequerel (GBq) of 177Lu-DOTATOC every 8-10 weeks. Cumulative activity: 18,5 e 27,75 GBq; Other Names: "MONO"; Radiation: Yttrium-90 (90Y)-DOTATOC; 5 cycles of 1,85 e 2,775 GBq of 90Y-DOTATOC every 8-10 weeks. Cumulative activity: 9,25 e 13,875 GBq; Radiation: 177Lu-DOTATOC + 90Y-DOTATOC; 3 cycles of 3,7 e 5,55 GBq of 177Lu-DOTATOC alternated with 2 cycles of 1,85 e 2,775 GBq of 90Y-DOTATOC every 8-10 weeks. Cumulative activity: 18,5 e 27,75 GBq of 177Lu-DOTATOC and 9,25 e 13,875 GBq of 90Y-DOTATOC; Other Names: "DUO"; Radiation: Re-treatment 177Lu-DOTATOC; 3 cycles of 3,7 e 5,55 GBq of 177Lu-DOTATOC every 8-10weeks. Cumulative activity: 11,1 e 16,65 GBq of 177Lu-DOTATOC; Radiation: Re-treatment 90Y-DOTATOC; 3 cycles of 1,85 e 2,775 GBq of 90Y-DOTATOC every 8-10 weeks Cumulative activity: 5,55 e 8,325 GBq of 90Y-DOTATOC
Experimental: Other Nets; 25 patients affected by non-functional and functional NETs arising from Skin, Thyroid (medullary thyroid and anaplastic cancer) and Parathyroids.	Radiation: Lutetium-177 (177Lu)-DOTATOC; 5 cycles of 3,7 e 5,55 gigabequerel (GBq) of 177Lu-DOTATOC every 8-10 weeks. Cumulative activity: 18,5 e 27,75 GBq; Other Names: "MONO"; Radiation: Yttrium-90 (90Y)-DOTATOC; 5 cycles of 1,85 e 2,775 GBq of 90Y-DOTATOC every 8-10 weeks. Cumulative activity: 9,25 e 13,875 GBq; Radiation: 177Lu-DOTATOC + 90Y-DOTATOC; 3 cycles of 3,7 e 5,55 GBq of 177Lu-DOTATOC alternated with 2 cycles of 1,85 e 2,775 GBq of 90Y-DOTATOC every 8-10 weeks. Cumulative activity: 18,5 e 27,75 GBq of 177Lu-DOTATOC and 9,25 e 13,875 GBq of 90Y-DOTATOC; Other Names: "DUO"; Radiation: Re-treatment 177Lu-DOTATOC; 3 cycles of 3,7 e 5,55 GBq of 177Lu-DOTATOC every 8-10weeks. Cumulative activity: 11,1 e 16,65 GBq of 177Lu-DOTATOC; Radiation: Re-treatment 90Y-DOTATOC; 3 cycles of 1,85 e 2,775 GBq of 90Y-DOTATOC every 8-10 weeks Cumulative activity: 5,55 e 8,325 GBq of 90Y-DOTATOC
Experimental: Cancers of Unknown Primary Origin (CUP) NETs; 25 patients affected by non-functional and functional unknown primary NETs	Radiation: Lutetium-177 (177Lu)-DOTATOC; 5 cycles of 3,7 e 5,55 gigabequerel (GBq) of 177Lu-DOTATOC every 8-10 weeks. Cumulative activity: 18,5 e 27,75 GBq; Other Names: "MONO"; Radiation: Yttrium-90 (90Y)-DOTATOC; 5 cycles of 1,85 e 2,775 GBq of 90Y-DOTATOC every 8-10 weeks. Cumulative activity: 9,25 e 13,875 GBq; Radiation: 177Lu-DOTATOC + 90Y-DOTATOC; 3 cycles of 3,7 e 5,55 GBq of 177Lu-DOTATOC alternated with 2 cycles of 1,85 e 2,775 GBq of 90Y-DOTATOC every 8-10 weeks. Cumulative activity: 18,5 e 27,75 GBq of 177Lu-DOTATOC and 9,25 e 13,875 GBq of 90Y-DOTATOC; Other Names: "DUO"; Radiation: Re-treatment 177Lu-DOTATOC; 3 cycles of 3,7 e 5,55 GBq of 177Lu-DOTATOC every 8-10weeks. Cumulative activity: 11,1 e 16,65 GBq of 177Lu-DOTATOC; Radiation: Re-treatment 90Y-DOTATOC; 3 cycles of 1,85 e 2,775 GBq of 90Y-DOTATOC every 8-10 weeks Cumulative activity: 5,55 e 8,325 GBq of 90Y-DOTATOC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Control Rate	Post-treatment evaluation will be performed with: a clinical examination;; a comparative morphological re-evaluation, using version 1.1 of Response evaluation criteria in solid tumors (RECIST criteria) on Computed Tomography (CT);; a comparative functional re-evaluation, performed both on 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission computed tomography (PET/CT) and Gallium-68 (68Ga)-DOTATOC PET/CT using visual and semi-quantitative parameters (such as SUVmax). Based on all these parameters, Disease Control Rate will be labelled as: Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progression Disease (PD).	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	Progression free survival is defined as the time intercurrent from treatment start to the date of first observation of documented disease progression or death due to any cause.	6 months
Overall Survival	Overall survival is defined as the time intercurrent from treatment start to the date of death due to any cause, or the date of last contact.	6 months
Evaluation of PRRT Safety	The evaluation of Treatment-Emergent Adverse Events, defined as any G3/G4 toxicity. The evaluation will be performed during every treatment cycle and after 12, 18, 24, 30, 36 and 42 months after the last treatment cycle and will be based on version 4.0 of Common Terminology Criteria for Adverse Events (CTC-AE) toxicity criteria.	6 months
Evaluation of Quality of Life	Quality of Life (QoL) will be evaluated with quality of life questionnaire, version 3 (QLQ-C30) by European Organisation for Research and Treatment of Cancer (EORTC). The questionnaire includes five functional scales, three symptom scales, a global health status / QoL scale, and six single items. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.	6 months

Collaborators and Investigators

• Sponsor: University Hospital of Ferrara

Publications and helpful links

General Publications

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Study record dates

Study Major Dates

• Study Start (Actual): July 2, 2018
• Primary Completion (Anticipated): June 30, 2023
• Study Completion (Anticipated): June 30, 2023

Study Registration Dates

• First Submitted: March 2, 2021
• First Submitted That Met QC Criteria: March 5, 2021
• First Posted (Actual): March 10, 2021

Study Record Updates

• Last Update Posted (Actual): March 10, 2021
• Last Update Submitted That Met QC Criteria: March 5, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: 177Lu; Neuroendocrine Tumors; 90Y; 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; Antineoplastic Agents; Gastrointestinal Agents; Antineoplastic Agents, Hormonal; Radiopharmaceuticals; Octreotide; Edotreotide; Edotreotide lutetium LU-177
• Other Study ID Numbers: 160990; 2016-005129-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No