Peptide Receptor Radionuclide Therapy With 177Lu-Dotatate Associated With Metronomic Capecitabine In Patients Affected By Aggressive Gastro-Etero-Pancreatic Neuroendocrine Tumors (LuX)

The aim of this phase I-II study is to evaluate the efficacy and toxicity of PRRT with 177Lu-DOTATATE (Lu-PRRT) associated to metronomic chemotherapy with Capecitabine in patients affected by aggressive FDG-positive gastro-entero-pancreatic NET. Moreover to analyze the effects of the capecitabine metronomic schedule on the level of circulating angiogenetic factors.

Study Overview

• Status: Active, not recruiting
• Conditions: Neuroendocrine Tumors; Gastro Entero Pancreatic Neuroendocrine Tumors
• Intervention / Treatment: Drug: 28 GBq 177Lu-DOTATATE; Drug: 22 GBq 177Lu-DOTATATE

Detailed Description

Neuroendocrine tumors (NETs) are relatively rare tumors, mainly originating from the digestive system, able to produce bioactive amines and hormones. NETs tend to be slow growing and are often diagnosed when metastatic. Treatment is multidisciplinary and should be individualized according to the tumor type, burden, and symptoms. Therapeutic tools include surgery, interventional radiology, and medical treatments such as somatostatin analogues, interferon, chemotherapy, new targeted drugs (everolimus, sunitinib) with radiolabelled somatostatin analogues. Despite the options available, antiproliferative treatment options for patients with inoperable gastro-entero-pancreatic (GEP) NETs are limited.

PRRT with radiolabelled somatostatin analogues 90Y-DOTATOC, and 177Lu-DOTATATE (177Lu-DOTA-D-Phe1-Tyr3-octreotate), has been experimented for more then 15 years in few centers. The introduction of PRRT and, particularly, the advent of 177Lu-DOTATATE, broke through the poor scenario of available treatment for NETs.

Dosimetric studies demonstrated that 90Y-DOTATOC and 177Lu-DOTATATE are able to deliver high radiation doses to somatostatin receptor sst2-expressing tumors and low doses to normal organs. Clinical studies demonstrated that partial and complete objective responses in up to 30% of patients can be obtained, with a great survival benefit including those with stable disease. Side effects may involve the kidney and the bone marrow and are usually mild. Renal protection is used to minimize the risk of a late decrease of renal function.

Recently, in order to further increase the objective response to PRRT, a combined treatment with the radiosensitizer capecitabine, has been proposed and tested on GEP-NET patients' population. Capecitabine is the oral prodrug of 5-fluorouracile (5-FU), which is active in GEP tumors and a radiosensitizer itself. The finding that neo-angiogenesis can be shut down also with cytotoxic drugs like capecitabine when administered in low and frequent doses, constitutes the rationale for proposing a particular schedule of chemotherapy that is, therefore, named "metronomic" or "anti-angiogenic".

Based on the reported experience, the investigators think to offer a combined therapy in aggressive, metabolically active tumors, such as those patients with a positive FDG scan. FDG-PET allow the investigators to obtain in vivo imaging of increased glycolysis which is known to be an hallmark of tumor aggressiveness.

The aim of this phase I-II study is to evaluate the efficacy and toxicity of PRRT with 177Lu-DOTATATE (Lu-PRRT) associated to metronomic chemotherapy with Capecitabine in patients affected by aggressive FDG-positive gastro-entero-pancreatic NET. Moreover to analyze the effects of the capecitabine metronomic schedule on the level of circulating angiogenetic factors.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy
    • Lisa Bodei
  • FC
    • Meldola, FC, Italy, 47014
      • Giovanni Paganelli

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:

• Histopathologic diagnosis of inoperable or metastatic gastro-entero-pancreatic neuroendocrine neoplasia.
• Conserved hematological, liver and renal parameters: haemoglobin >= 10 g/dL, absolute neutrophil count (ANC) >= 1.5 x 109 /L, platelets >= 100 x 109 /L, bilirubin ≤1.5 X UNL (upper normal limit), ALT <2.5 X UNL (< 5 X UNL in presence of liver metastases), creatinine < 2 mg/dL.
• Age more than 18 years.
• Patients with documented disease will be admitted to therapeutic phase only if the diagnostic receptor imaging (OctreoScan) demonstrate a significant uptake in the tumor (grade 2 or 3, according to a preset scoring, where grade 1= equal to normal liver, grade2 = higher than normal liver, grade 3= higher than kidneys and spleen), that may allow delivering a low absorbed dose to normal organs and a high dose to the tumor.
• Patients with documented disease will be admitted to therapeutic phase only if the 18FDG PET/CT is positive with a SUV > 2.5 at least in one documented lesion.
• Disease must be measurable by means of conventional imaging (CT or MRI).
• Before treatment clinical history data will be collected, physical examination will be performed and diagnostic and laboratory data will be examined.
• Patients must not receive other treatments (e.g. chemo- or radiotherapy) from one month before to two months after the completion of 177Lu-DOTATATE cycles.
• Patients must be naive from previous radionuclide treatments with radiopeptides (e.g. 111Inpentetreotide, 90Y-DOTATOC) or other radiopharmaceuticals (e.s. 131I-MIBG, 131I).

Exclusion Criteria:

• Pregnancy/breastfeeding (a pregnancy test not older than 7 days is mandatory).
• Assessed bone marrow invasion > 25%.
• Other concomitant neoplasm (excluding in situ basaliomas and radically treated cervical cancers).
• ECOG score higher than 2.
• Expectancy of life shorter than 6 months.
• Patients with psycho-physical conditions that are not suitable for entering this clinical study and fulfilling its requirements.

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 28 GBq 177Lu-DOTATATE; 5 cycles of 5.5 GBq (150 mCi) each, up to the total cumulative activity of 28 GBq (750 mCi) 177Lu-DOTATATE	Drug: 28 GBq 177Lu-DOTATATE; Patients without risk factors (particularly long standing and poorly controlled diabetes and hypertension) for late renal toxicity will be administered with 5 cycles of 5.5 GBq (150 mCi) each, up to the total cumulative activity of 28 GBq (750 mCi) of 177Lu-DOTATATE.
Experimental: 22 GBq 177Lu-DOTATATE; 6 cycles of 3.7 GBq (100 mCi) each, up to the total cumulative activity of 22 GBq (600 mCi) 177Lu-DOTATATE	Drug: 22 GBq 177Lu-DOTATATE; Patients with risk factors for late renal toxicity will be administered with 6 cycles of 3.7 GBq (100 mCi) each, up to the total cumulative activity of 22 GBq (600 mCi)177Lu-DOTATATE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Overall Response Rate	rate of objective clinical response (complete response (CR), partial response (PR), or minor response (MR) according to RECIST criteria	up to 24 months
toxicity rate	The rate of toxicity, either acute or delayed, according to NCI criteria, of the association 177Lu-DOTATATE and metronomic capecitabine.	up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival in association with histopathology characteristics	evaluation of the PFS and the possible association between histopathology characteristics (grading and proliferation index)	up to 24 months
Progression free survival in association with the receptor and metabolic status at OctreoScan and FDG PET	Progression free survival in association with the receptor and metabolic status at OctreoScan and FDG PET	up to 24 months

Collaborators and Investigators

• Sponsor: Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
• Collaborators: Istituto Europeo di Oncologia IEO MILANO
• Investigators: Principal Investigator: Giovanni Paganelli, MD, IRST IRCCS, Meldola (FC)

Study record dates

Study Major Dates

• Study Start (Actual): September 2, 2015
• Primary Completion (Actual): April 1, 2017
• Study Completion (Anticipated): June 1, 2021

Study Registration Dates

• First Submitted: April 7, 2016
• First Submitted That Met QC Criteria: April 7, 2016
• First Posted (Estimate): April 13, 2016

Study Record Updates

• Last Update Posted (Actual): February 26, 2021
• Last Update Submitted That Met QC Criteria: February 25, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: neuroendocrine tumors; gastro entero pancreatic neuroendocrine tumors; Radioisotope therapy; 177Lu-DOTATATE; METRONOMIC CAPECITABINE
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Pancreatic Diseases; Adenoma; Pancreatic Neoplasms; Neoplasms; Neuroendocrine Tumors; Adenoma, Islet Cell; Molecular Mechanisms of Pharmacological Action; Radiopharmaceuticals; Lutetium Lu 177 dotatate
• Other Study ID Numbers: IRST100.19