Evaluatioon of 177Lu-TATE-EB-01（LNC1010）in SSTR2-positive Tumors

Study Overview
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Brief Summary
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177Lu-LNC1010(177Lu-EB-TATE-01) is a radiotherapeutic drug indicated in subjects with unresectable, metastatic somatostatin receptor (SSTR) positive neuroendocrine tumors (NETs). In this study, we designed and developed a new radioligand, EB-TATE-01 (second generation long-acting EB-TATE formula), through combining EB and altering the linker to further improve the pharmacokinetics and pharmacodynamics, leading to substantially enhanced radioligand therapy effect. This is an open-label, non-controlled, non-randomized study to investigate the long-lasting radiolabeled somatostatin analogue based peptide receptor radionuclide therapy and evaluate response to 177Lu-LNC1010 in patients with advanced SSTR2-positive tumors. Different groups with doses of 2.22GBq (60 mCi), 3.7GBq (100mCi) and 5.18GBq (140mCi) of 177Lu-LNC1010 will be injected intravenously. All patients will undergo 68Ga-DOTA-Octreotide(TATE) PET/CT scans before and after the treatment.

Detailed Description
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Somatostatin receptor(SSTR), especially SSTR subtype 2 (SSTR2),has been a popular target for molecular imaging and radionuclide therapy in recent years. SSTR antagonists, such as LNC1010, have emerged as a new type of somatostatin analog, characterized by a low internalization rate and high tumor affinity. 68Ga-DOTA(68Ga-DOTA)-LNC1010 has been reported that it showed favorable biodistribution, high tumor uptake, and good tumor retention, resulting in high image contrast. SSTR2 has been found highly expressed in SSTR2-positive tumors, indicating the feasibility of Positron Emission Tomography（PET)/ CT with 68Ga-DOTA-conjugated peptides for imaging SSTR2 expression and peptide-receptor radionuclide therapy (PRRT) for the treatment option in SSTR2-positive tumors. However, a major problem in the therapeutic use of 177Lu-DOTA(177Lu-DOTA)-LNC1010 has been its short half-life and fast rate of clearance. This study was designed to evaluate the efficacy of a long-lasting radiolabeled somatostatin analogue 177Lu-LNC1010 in patients with SSTR2-positive tumors.

Official Title
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A Phase 1, Non-Randomized, Open-Label, Dose Escalation, Single-Center Study to Determine the Safety, Bio-distribution, and Preliminary Effectiveness of 177Lu-TATE-EB-01（LNC1010）in Adult Subjects With SSTR2-positive Tumors

Conditions
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SSTR2-positive Tumors

Intervention / Treatment
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* Drug: 177Lu-LNC1010 1
* Drug: 177Lu-LNC1010 2
* Drug: 177Lu-LNC1010 3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 years or older; Histologically proven or cytologically confirmed, inoperable, NPC, and SSTR positive cancers; Measurable disease as defined by Response Criteria in Solid Tumors (RECIST) version 1.1; Overexpression of somatostatin receptors of the target lesions at 68Ga-DOTA-TATE positron emission tomography (PET)/computed tomography (CT) with standard uptake value(SUV) of lesions greater than normal liver in at least 1 lesion; Patients who were able to provide informed consent (signed by participant, parent or legal representative) and assent according to the guidelines of the Clinical Research Ethics Committee. Exclusion Criteria: Women who are pregnant or breastfeeding; History of allergic reactions attributed to compounds of similar chemical or biologic composition to 177Lu-EB-TATE as assessed from medical records; Previous radioligand treatment with 177Lu-DOTA-TATE; Participant has had prior chemotherapy, targeted cancer therapy, immunotherapy, or treatment with an investigational anticancer agent within 4 weeks or 4 half-lives whichever is longer, before the first administration of study drug; Participant has not fully recovered from major surgery or significant traumatic injury prior the first dose of study drug or expects to have major surgery during the study period or within 3 months after the last dose of study drug; Life expectancy < 3 months as assessed by the treating physician; Uncontrolled, intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; The inability or unwillingness of the research participant, parent or legal representative to provide written informed consent.

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
Interventional Model Description: To evaluate response to the different groups with doses of 2.22 GBq(60 mCi) and 3.7 GBq (100 mCi) and 5.18 GBq (140mCi) of 177Lu-LNC1010 in patients with advanced metastatic NPCs.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 177Lu-LNC1010 1<br>The patients were intravenously injected with single dose 2.22GBq (60 mCi) of 177Lu-LNC1010 and underwent 68Ga-DOTA-TATE PET/CT scans before and after the treatment. | Drug: 177Lu-LNC1010 1<br>* The patients were intravenously injected with single dose 2.22GBq (60 mCi) of 177Lu-LNC1010 and underwent 68Ga-DOTA-TATE PET/CT scans before and after the treatment.<br>|
| Experimental: 177Lu-LNC1010 2<br>The patients were intravenously injected with single dose 3.7GBq (100 mCi) of 177Lu-LNC1010 and underwent 68Ga-DOTA-TATE PET/CT scans before and after the treatment. | Drug: 177Lu-LNC1010 2<br>* The patients were intravenously injected with single dose 3.7GBq (100 mCi) of 177Lu-LNC1010 and underwent 68Ga-DOTA-TATE PET/CT scans before and after the treatment.<br>|
| Experimental: 177Lu-LNC1010 3<br>The patients were intravenously injected with single dose 5.18 GBq (140mCi) of 177Lu-LNC1010 and underwent 68Ga-DOTA-TATE PET/CT scans before and after the treatment. | Drug: 177Lu-LNC1010 3<br>* The patients were intravenously injected with single dose 5.18GBq (140 mCi) of 177Lu-LNC1010 and underwent 68Ga-DOTA-TATE PET/CT scans before and after the treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | 68Ga-Fibroblast activation protein inhibitor 46 and 18F-fluorodeoxyglucose will be performed for efficacy evaluation by RECIST 1.1 and PERCIST. Particularly, 68Ga-FAPI-46 will be performed at baseline and beginning of each circle, and 2 weeks after the last treatment. 18F-FDG will be performed at baseline and 2 weeks after the last treatment. | From date of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months. | 
| Incidence of treatment-related adverse events (safety and tolerability) | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0. | From date of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Progression-free survival is defined as the time from the date of first dose to the date of the first documented radiological progression or death due to any cause. | baseline, every 8 weeks up to 1 year after last patient first treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SSTR2-positive tumors, 177Lu, LNC1010, SSTR antagonist