177Lu-DOTA-EB-TATE in Adult Patients With Advanced, Well- Differentiated Neuroendocrine Tumors

Phase I, Open-Label Study of the Safety and Dosimetry of a 3-Dose Regimen of Escalating Doses of 177Lu-DOTA-EB-TATE in Adult Patients With Advanced, Well- Differentiated Neuroendocrine Tumors

This is a Phase I clinical trial to assess the safety and dosimetry profiles of 177Lu-DOTA-EB-TATE in patients with advanced, metastatic or inoperable, somatostatin receptor-positive, well-differentiated GEP-NETs.

The treatment regimen will consist of a single-dose intravenous administration of 177Lu-DOTA-EB-TATE per 6-week cycle, for a total of 2 cycles. The dose per cycle will be fixed for each patient and will be escalated in 3 different dose levels, from 50 mCi to 150 mCi (1.85 -5.55 GBq). Each dose of 177Lu-DOTA-EB-TATE will be administered in association with intravenous renal protective amino acid solutions.

Peptide Receptor Radionucleotide Therapy ( PRRT) using 177Lu-DOTA-EB-TATE with a defined number of cycles will be administered.

The Amino acid solution to be used in this study will contain a mixture of lysine and arginine diluted in an electrolyte solution.

To evaluate the safety of 177Lu-DOTA-EB-TATE assessed from the number of patients with treatment-related adverse events.

To identify the dose-limiting toxicities (DLTs) of escalating doses of 177Lu-DOTA-EB-TATE up to 150 mCi.

To evaluate the differential safety of 177Lu-DOTA-EB-TATE, expressed as the number of patients with treatment-related adverse events following 177Lu-DOTA-EB-TATE.

Inclusion Criteria: Ability to understand and willing to sign a written informed consent document Aged 18 years or older Histologically proven or cytologically confirmed, inoperable, GEP-NETs Neuroendocrine tumors (NETs) of grade 1, 2 and 3 according to World Health Organization (WHO) 2017 classification Measurable disease as defined by Response Criteria in Solid Tumors (RECIST) version 1.1 Overexpression of somatostatin receptors of the target lesions in 68Ga-DOTA-TATE positron emission tomography (PET)/computed tomography (CT) with SUV of lesions greater than normal liver in at least 1 lesion A Cockcroft Gault calculated creatinine clearance > 60 mL/min Karnofsky performance status scale ≥ 70% Women of childbearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation, including follow-up (7 months after the last dose of study drug for women and 4 months for men). Previous local therapy (e.g., chemoembolization or bland embolization) is allowed if completed >4 weeks prior to study entry. Previous surgery no less than 6 weeks prior to study entry. Either no prior treatment with 177Lu-DOTA-TATE or at least 12 months progression-free survival (PFS) after prior treatment with 177Lu-DOTA-TATE Exclusion Criteria: Women who are pregnant or breastfeeding History of allergic reactions attributed to compounds of similar chemical or biologic composition to 177Lu-DOTA-EB-TATE as assessed from medical records Previous treatment with more than 4 cycles of 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 < 6 months as assessed by the treating physician > 80% liver involvement by tumor > 25% bone marrow involvement by tumor Poorly differentiated neuroendocrine neoplasms, such as poorly differentiated neuroendocrine carcinoma, small- and large-cell neuroendocrine carcinoma; mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN); Grade 3 neuroendocrine carcinomas (NEC) Presence of somatostatin receptor negative lesions if they cannot be addressed with loco-regional therapies prior to the treatment start Deteriorated renal function, as indicated by a serum creatinine clearance > 1.7 mg/dL Deteriorated bone marrow function Deteriorated liver function Toxicities from prior therapies that have not resolved to grade 1 or grade 0 Active and clinically significant bacterial, fungal, or viral infection, including hepatitis B (HBV), hepatitis C (HBC), know human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-related illness Known brain metastases and/or carcinomatous meningitis, unless these metastases have been treated and stabilized Uncontrolled diabetes mellitus as defined by a HbA1c >9% Impossibility to interrupt short-acting octreotide for 24 h before and 24 h after the administration of 177Lu-DOTA-EB-TATE; impossibility to have an interval of ≥4 weeks between octreotide and 177Lu-DOTA-EB-TATE The use of somatostatin and its analogues within 4 months of a planned 177Lu-DOTA-EB-TATE treatment 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 Prior external beam radiation therapy involving >25% of the bone marrow Unmanageable urinary incontinence rendering the administration of 177Lu-DOTA-EB-TATE unsafe Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and with no evidence of recurrence