Treatment Using 177Lu-DOTA-EB-TATE in Patients With Advanced Neuroendocrine Tumors

Study Overview
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Brief Summary
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This is a prospective study to investigate the long-lasting radiolabeled somatostatin analogue based peptide receptor radionuclide therapy and evaluate response to 177Lu-DOTA-EB-TATE in patients with advanced metastatic neuroendocrine tumors. Different groups with doses of 0.37GBq-0.74GBq (10-20 mCi) and 1.85GBq (50 mCi)of 177Lu-DOTA-EB-TATE, 3.7GBq (100 mCi)of 177Lu-DOTA-TATE will be injected intravenously. Besides, we evaluated the safety and dosimetry of 3.7GBq (100 mCi) of 177Lu-DOTA-EB-TATE with and without amino acid infusion. All patients will undergo 68Ga-DOTATATE PET/CT scans before and after the treatment.

Detailed Description
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Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms that can develop anywhere in the body and arise from neuroendocrine cells throughout the endocrine system. The most recent NCCN guidelines for unresectable and metastatic NET recommend somatostatin analogues as first-line treatment, but do not recommend a particular treatment sequence for the remaining therapies. Radiolabeled somatostatin analogue therapy, also known as peptide receptor radionuclide therapy has become a well-accepted treatment for patients with well to moderately differentiated unresectable or metastatic NETs and disease progression after first-line treatment. However, a major problem in the therapeutic use of 177Lu-Dotatate has been its short half-life and fast rate of clearance. Kidney is considered one of the dose-limiting organs in peptide receptor radionuclide therapy (PRRT). Amino acid has been infused to reduce renal absorbed dose by inhibiting the proximal tubular reabsorption of the radiopeptide. This study was designed to compare the efficacy of a long-lasting radiolabeled somatostatin analogue 177Lu-DOTA-EB-TATE with 177Lu-DOTA-TATE in patients with advanced metastatic neuroendocrine tumors and evaluate the safety and dosimetry of 3.7GBq (100 mCi) of 177Lu-DOTA-EB-TATE with and without amino acid infusion.

Official Title
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Treatment of a Long-lasting Radiolabeled Somatostatin Analogue 177Lu-DOTA-EB-TATE in Patients With Advanced Metastatic Neuroendocrine Tumors

Conditions
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Neuroendocrine Tumors

Intervention / Treatment
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* Drug: 177Lu-DOTA-EB-TATE 1
* Drug: 177Lu-DOTA-TATE
* Drug: 177Lu-DOTA-EB-TATE 2
* Drug: 177Lu-DOTA-EB-TATE 3
* Drug: 3.7 GBq (100 mCi) of 177Lu-DOTA-EB-TATE with amino acids (lysine and arginine)
* Drug: 3.7 GBq (100 mCi) of 177Lu-DOTA-EB-TATE without amino acids (lysine and arginine)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults who had neuroendocrine tumors and had metastasized, that were with histologically confirmed, inoperable and had showed disease progression according to Response Evaluation Criteria in Solid Tumors [RECIST]. Tumors were with well-differentiated histologic features and a Ki67 index of 0 to 20%. Target tumors were selected from CT, MRI, and 68Ga-DOTA-TATE PET/CT, with confirmed somatostatin receptorexpressing and at least one lesion has higher uptake than that of normal liver parenchyma on 68Ga-DOTA-TATE PET imaging within 1 weeks. Exclusion Criteria: The exclusion criteria were a serum creatinine level of more than 150 μmol per liter, baseline measured GFR of less than 50 mL/min/1.73 m2, determined by 99mTc-DTPA renal function examination, a hemoglobin level of less than 8.0 g/dl, a white-cell count of less than 2.0× 109/L, a platelet count of less than 75 × 109/L, a total bilirubin level of more than 3 times the upper limit of the normal range and a serum albumin level of more than 3.0 g per deciliter, cardiac insufficiency including carcinoid heart valve disease, a severe allergy or hypersensitivity to radiographic contrast material, claustrophobia, and pregnancy or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 177Lu-DOTA-EB-TATE 1<br>The patients were intravenously injected with single dose 0.37GBq-0.74GBq (10-30 mCi) of 177LuDOTA-EB-TATE and underwent 68Ga-DOTATATE PET/CT scans before and after the treatment. | Drug: 177Lu-DOTA-EB-TATE 1<br>* The patients were intravenously injected with single dose 0.37GBq-0.74GBq (10-30 mCi) of 177Lu-DOTA-EB-TATE and underwent 68Ga-DOTATATE PET/CT scans before and after the treatment.<br>|
| Experimental: 177Lu-DOTA-EB-TATE 2<br>The patients were intravenously injected with single dose 1.85GBq (50 mCi) of 177LuDOTA-EB-TATE and underwent 68Ga-DOTATATE PET/CT scans before and after the treatment. | Drug: 177Lu-DOTA-EB-TATE 2<br>* The patients were intravenously injected with single dose 1.85GBq (50 mCi) of 177Lu-DOTA-EB-TATE and underwent 68Ga-DOTATATE PET/CT scans before and after the treatment.<br>|
| Experimental: 177Lu-DOTA-EB-TATE 3<br>The patients were intravenously injected with single dose 3.7 GBq (100 mCi) of 177LuDOTA-EB-TATE and underwent 68Ga-DOTATATE PET/CT scans before and after the treatment. | Drug: 177Lu-DOTA-EB-TATE 3<br>* The patients were intravenously injected with single dose 3.7GBq (100 mCi) of 177Lu-DOTA-EB-TATE and underwent 68Ga-DOTATATE PET/CT scans before and after the treatment.<br>|
| Experimental: 177Lu-DOTA-TATE<br>The patients were intravenously injected with single dose 3.7 GBq (100 mCi) of 177LuDOTA-TATE and underwent 68Ga-DOTATATE PET/CT scans before and after the treatment. | Drug: 177Lu-DOTA-TATE<br>* The patients were intravenously injected with single dose 3.7GBq (100 mCi) of 177Lu-DOTA-TATE and underwent 68Ga-DOTATATE PET/CT scans before and after the treatment.<br>|
| Experimental: 3.7 GBq (100 mCi) of 177Lu-DOTA-EB-TATE with amino acids (lysine and arginine)<br>The patients were intravenously injected with 3.7 GBq (100 mCi) of 177LuDOTA-TATE and amino acids (lysine and arginine). | Drug: 3.7 GBq (100 mCi) of 177Lu-DOTA-EB-TATE with amino acids (lysine and arginine)<br>* The patients were intravenously injected with 3.7GBq (100 mCi) of 177Lu-DOTA-EB-TATE and amino acids (lysine and arginine).<br>|
| Experimental: 3.7 GBq (100 mCi) of 177Lu-DOTA-EB-TATE without amino acids (lysine and arginine)<br>The patients were intravenously injected with 3.7 GBq (100 mCi) of 177LuDOTA-TATE without amino acids (lysine and arginine). | Drug: 3.7 GBq (100 mCi) of 177Lu-DOTA-EB-TATE without amino acids (lysine and arginine)<br>* The patients were intravenously injected with 3.7GBq (100 mCi) of 177Lu-DOTA-EB-TATE without amino acids (lysine and arginine).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of standardized uptake value of 68Ga-DOTA-TATE before and after the treatment in metastatic neuroendocrine tumors | The semiquantitative analysis will be performed by the same person for all the cases, and the standardized uptake value before and after the treatment in metastatic neuroendocrine tumors will be measured. | 1 year | 
| the safety of 3.7GBq of 177Lu-DOTA-EB-TATE with and without amino acid infusion. | Hematological parameters, liver, and renal function at baseline, 1 week and 4 weeks after PRRT were tested. 99mTc-DTPA dynamic renal imaging for the determination of the glomerular filtration rate (GFR) was performed at baseline and 8 weeks after each cycle of PRRT. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the dosimetry of 3.7GBq of 177Lu-DOTA-EB-TATE with and without amino acid infusion. | the absorbed dose for kidney and whole-body evaluated through HERMES software. | 1 year |