Intra-arterial Lutetium-177-dotatate for Treatment of Patients With Neuro-endocrine Tumor Liver Metastases

The objective is to investigate the impact of intra-arterial administration of 177Lu-dotatate on the intrahepatic biodistribution in patients with NET liver metastases. Our primary objective is to evaluate if there is a difference in post-treatment tumor-to-non-tumor (T/N) activity concentration ratio on SPECT/CT between the intra-arterial treated liver lobe and the intravenous treated liver lobe.

Rationale: The majority of neuroendocrine tumor (NET) patients present with metastases, most often including liver metastases. These patients have a poorer prognosis and lower quality of life.

Currently, intravenous administered somatostatin-bound radionuclides (177Lu-dotatate) have shown to improve tumor response rates and progression free survival (PFS). Despite of the increased tumor response rate and PFS, liver metastases still remain the major cause of morbidity and mortality in these patients. Patients with liver metastases have a worse outcome in terms of overall survival after treatment with 177Lu-dotatate compared to patients with limited or no liver metastases.

Objective: to investigate the impact of intra-arterial (IA) administration of 177Lu-dotatate on the intrahepatic biodistribution in patients with NET liver metastases. Our primary objective is to evaluate if there is a difference in post-treatment tumor-to-non-tumor (T/N) activity concentration ratio on SPECT/CT between the intra-arterial treated liver lobe and the intravenous treated liver lobe.

Study design: Multicenter, interventional, block randomized, phase 2 clinical trial. We use a within-subject controlled design where the administration of 177Lu-dotatate is randomized between the right or left hepatic artery. Selective IA administration of 177Lu-dotatate allows for intra-patient comparison between IA administration (one lobe) versus IV 'administration' (the other lobe). The contralateral liver lobe and the rest of the body receive treatment by second pass IV route.

Study population: 26 patients with NET liver metastases (\> 18 years old). Intervention: Treatment will be randomized between selective right or left hepatic artery administration of 177Lu-dotatate (Four administrations of 7.4 GBq; each via the same randomly allocated hepatic artery during angiography).

Main study parameters/endpoints: To assess if there is a difference in post-treatment tumor-to-non-tumor (T/N) activity concentration ratio on SPECT/CT between the intra-arterial treated liver lobe and the intravenous treated liver lobe. The T/N activity concentration will be measured on SPECT/CT. The primary endpoint will be assessed after the first treatment cycle. The T/N activity ratios of the second, third, and final treatment cycle will be assessed as secondary endpoint. Tumor response, toxicity, extrahepatic uptake and kidney uptake are secondary endpoints. Intra- and inter-patient differences will be studied.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: As with the standard IV treatment with 177Lu-dotatate, the treatment consists of four cycles. During each cycle, patients will be admitted for 1 night and undergo physical examination, laboratory examination, angiography with administration of the treatment dose, and post-treatment imaging. Risks include standard complication risks related to angiography (bleeding or infection). No additional risks with relation to the treatment itself are expected compared to the standard IV treatment (nausea, vomiting).

Eligibility Criteria:
Inclusion Criteria:

* Patients must have given written informed consent.
* Female or male aged 18 years and over.
* Inoperable histologically proven neuro-endocrine tumor with indication for 177Lu-dotatate at enrollment time.
* Well-differentiated neuro-endocrine tumor with a Ki67-index ≤20% and a mitotic count of ≤20.
* Confirmed presence of somatostatin receptors on target lesions, based on somatostatin receptor imaging.
* Life expectancy of 6 months or longer.
* Eastern Cooperative Oncology Group (ECOG) performance score 0-1.
* Hepatic metastases with at least one lesion ≥3 cm on cross sectional imaging in both the right and left liver lobe (i.e. left and right lobes are based on the hepatic arterial perfusion territory).
* Presence of excessive liver metastases, defined as \>25% tumor load, with or without extrahepatic metastases.
* Patients must have clinical or radiological progressive disease.
* Negative pregnancy test for women of childbearing potential.

Exclusion Criteria:

* Any previous radioembolization, chemoembolization, or bland embolization, at any time, or surgery or radiofrequency ablation (or other ablative therapies) within 12 weeks prior to randomization in the study.
* Prior external beam radiation therapy to the liver.
* Interferons, Everolimus (mTOR-inhibitors) or other systemic therapies within 4 weeks prior to randomization in the study.
* Any patient receiving treatment with short-acting Octreotide, which cannot be interrupted for 24 hours before and 24 hours after the administration of 177Lu-dotatate, or any patient receiving treatment with Octreotide LAR, which cannot be interrupted for at least 4 weeks before the administration of 177Lu-dotatate, unless the tumor uptake on target lesions observed by imaging during continued Octreotide LAR treatment is higher than normal liver uptake.
* Any unresolved toxicity greater than National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE version 4.03) grade 2 from previous anti-cancer therapy.
* Serum bilirubin \> Upper Limit of Normal (ULN), serum albumin \<3.0 g/dL.
* Glomerular filtration rate \<50 ml/min.
* Hb \<5.5 mmol/L; leucocytes \<3.0x109/L; platelets \<100x109/L (at baseline; 75x109/L is sufficient for cycles 2-4).
* Uncontrolled congestive heart failure (NYHA II, III, IV).
* Uncontrolled diabetes mellitus.
* Patients suffering from diseases with an increased chance of liver toxicity.
* Patients suffering from psychic disorders that make a comprehensive judgement impossible, such as psychosis, hallucinations and/or depression. Patients who are declared incompetent.
* Previous enrolment in the present study or previous treatment with 177Lu-dotatate.
* Female patients who are not using an acceptable method of contraception (oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, intrauterine device or tubal ligation) OR are less than 1 year postmenopausal or surgically sterile during their participation in this study (from the time they sign the consent form) to prevent pregnancy.
* Male patients who are not surgically sterile or do not use an acceptable method of contraception during their participation in this study (from the time they sign the consent form) to prevent pregnancy in a partner.
* Body weight over 150 kg.
* Current spontaneous urinary incontinence.
* Severe allergy for i.v. contrast (Visipaque®), used for CT evaluation and treatment angiography.