Lutathera for the Treatment of Unresectable Gastroenteropancreatic Neuroendocrine Tumors That Have Spread to the Liver
This phase I trial investigates if it is safe and possible to give Lutathera directly into an artery of the liver (hepatic intra-arterial infusion) in treating patients with gastroenteropancreatic neuroendocrine tumors that cannot be removed by surgery (unresectable) and have spread to the liver. Lutathera is a medication that gives off small amounts of radiation (radioactive medication), and doctors use it to treat different types of neuroendocrine tumors. However, doctors normally give the medication to people through a vein in the arm (intravenous infusion). Giving Lutathera via hepatic intra-arterial infusion may give a greater dose of radiation to the liver tumors for patients with gastroenteropancreatic neuroendocrine tumors.
Inclusion Criteria
- Ability to understand and willingness to sign a written informed consent document
- Histologically proven or cytologically confirmed, non-resectable, gastroenteropancreatic (GEP), bronchial or unknown primary neuroendocrine tumors (NETs) with liver-dominant disease with or without prior treatment with embolization
- Measurable disease as defined by RECIST 1.1 with at least one dimension >= 1.0 cm
- GEP or unknown primary NET of grade 1, 2 and 3 according to World Health Organization (WHO) 2017; typical or atypical lung carcinoid according to the Travis classification of 2004
- Progression of disease defined by one of the following occurring within 6 months of study entry: * At least a 20% increase in radiologically or clinically measurable disease * Appearance of any new lesion * Symptomatic disease (including worsening hormonal symptoms or symptoms related to tumor burden)
- Overexpression of somatostatin receptors of the target lesions at 68Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) with standardized uptake value (SUV) of lesions greater than normal liver at least in 1 metastasis
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky >= 70%)
- Women of childbearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation
- Previous local therapy (e.g., chemoembolization or bland embolization) is allowed if completed > 6 weeks prior to study entry. For such patients, there must be either progression of measurable disease documented within the treatment field, or measurable progressive disease outside the treatment field prior to study entry
- Previous oral chemotherapy, biotherapy (such as interferons or everolimus) and/or investigational agents are allowed if completed > 4 weeks prior to study entry. For patients who received systemic therapy prior to study entry, there must be documented progression of measurable disease since receiving systemic therapy prior to study entry
- Patients must not be candidate for potentially curative surgery. Prior surgery is allowed no less than 6 weeks prior to study entry. Note: Patients who have disease that is amendable to resection but who are not a surgical candidate for other medical reasons would be permitted
Exclusion Criteria
- Women who are pregnant or breastfeeding
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to 177Lu-DOTATATE as assessed from medical records
- Life expectancy < 6 months as assessed by the treating physician
- Over 80% liver involvement by tumor per the judgement of the radiologist
- Poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinoma), small and large cell type; mixed neuroendocrine-nonneuroendocrine neoplasm (MiNEN)
- Presence of somatostatin receptor negative lesions
- Prior treatment with other radiolabeled somatostatin analogs
- Prior systemic chemotherapy, except oral chemotherapy with capecitabine + temozolomide
- Contraindication to angiography/embolization including: * Patients cannot receive contrast * Severe allergic reaction to contrast despite premedication. Patients in who IV contrast is contraindicated are recommended to have magnetic resonance imaging (MRI) abdomen and noncontrast chest CT scan * Poor renal function not on dialysis * Other, based on judgment of the investigator
- Main portal vein tumor thrombus
- Deteriorated renal function: * Serum creatinine > 1.7 mg/dL OR * Estimated glomerular filtration rate (EGFR) < 30 ml/min
- Hemoglobin (Hb) < 8.0 g/dL
- White blood cell (WBC) < 3000/mm^3
- Absolute neutrophil count (ANC) < 1500/mm^3
- Platelets < 75.000/mm^3
- International normalized ratio (INR) > 2.0 for patients that are not on Coumadin or Xarelto
- Partial thromboplastin time (PTT) > 2 x upper limit of normal (ULN)
- Total bilirubin > 3 mg/dl
- Serum albumin < 3.0 g/dL unless prothrombin time is within the normal range
- Clinically relevant toxicities from prior therapies that have not resolved to grade 1 or grade 0
- Previous liver radioembolization with 90Y-microspheres
- Known brain metastases and/or carcinomatous meningitis, unless these metastases have been treated and stabilized
- Uncontrolled diabetes mellitus
- Inability to interrupt short-acting octreotide for 24 hour (h) before and 24 h after the administration of 177Lu-DOTATATE; inability to have an interval between octreotide LAR and 177Lu-DOTATATE of >= 4 weeks
- 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-DOTATATE 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
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04544098.
PRIMARY OBJECTIVE:
I. Feasibility of hepatic intra-arterial administration of lutetium Lu 177 dotatate (177Lu-DOTATATE [Lutathera]).
SECONDARY OBJECTIVES:
I. Adverse event profiles of hepatic intra-arterial administration of 177Lu-DOTATATE.
II. Compare the pharmacokinetics and biodistribution of 177Lu-DOTATATE after hepatic intra-arterial and intravenous administration.
III. Compare the tumor and normal organ dosimetry of 177Lu-DOTATATE after hepatic intra-arterial and intravenous administration.
IV. Compare the differential uptake of gallium Ga 68-HA-DOTA-TATE (68Ga-DOTATATE) after hepatic intra-arterial and intravenous administration.
V. Preliminarily evaluate the objective responses (partial and complete) and stable disease rate according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 (per patient analysis).
VI. Evaluate whether tumor dosimetry (per lesion analysis) correlates with the response per RECIST criteria.
EXPLORATORY OBJECTIVE:
I. Evaluate the correlation between the course of the safety parameters, such as complete blood count (CBC) and comprehensive metabolic panel (CMP), to the doses delivered to the single organs.
OUTLINE:
Patients receive lutetium Lu 177 dotatate via hepatic intra-arterial infusion over 30-40 minutes (cycles 1-2) and intravenously (IV) (cycles 3-4). Treatment repeats every 2 months for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 2 weeks for 2-3 months and then every 4 weeks for 4-6 months.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorLisa Bodei
- Primary ID20-232
- Secondary IDsNCI-2020-07133
- ClinicalTrials.gov IDNCT04544098