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Lutetium Lu 177 dotatate

Holmium-166 microspheres hepatic radioembolization, adjuvant to systemic 177Lu-dotatate.

Holmium-166 microspheres hepatic radioembolization.

Marnix G Lam, MD, PhD

Patients with gastroenteropancreatic neuroendocrine tumours (NET) often die from intrahepatic disease or are excluded from liver-directed treatment because of extrahepatic disease. Adjuvant liver-directed treatment is warranted to control both intra- and extrahepatic disease. Patients with liver metastases of NET will be included in this study (n = 30-48).The efficacy and toxicity of adjuvant 166Ho-radioembolization (166Ho-RE) after systemic 177Lu-dotatate will be studied in a non-comparative phase II study. The study is an interventional, treatment, non-randomized, open label, non-comparative, phase II study. 166Ho-RE will be performed via a catheter during angiography.

Acronym :

Holmium Embolization Particles for Arterial Radiotherapy Plus 177Lu-dotatate in Salvage NET patients- HEPAR PLUS-trial.

Rationale:

Patients with gastroenteropancreatic neuroendocrine tumours (NET) often die from intrahepatic disease or are excluded from liver-directed treatment because of extrahepatic disease. Adjuvant liver-directed treatment is warranted to control both intra- and extrahepatic disease.

Objective:

Primary objectives:

* To evaluate efficacy of adjuvant 166Ho-radioembolization (166Ho-RE) after systemic 177Lu-dotatate in a non-comparative phase II study.
* To establish the safety and toxicity profile of adjuvant 166Ho-RE after systemic treatment with 177Lu-dotatate.

Secondary objectives:

* To evaluate Quality of Life (QoL).
* To evaluate biodistribution / dosimetry.

Study design:

Interventional, treatment, non-randomized, open label, non-comparative, phase II study.

Study population:

Patients with liver metastases of NET will be included in this study (n = 30-48). These male and female patients must be aged ≥18 years. All NET histologies are acceptable, provided no standard therapeutic options are available, such as chemotherapy and surgery.

Intervention:

166Ho-RE will be performed via a catheter during angiography.

Study endpoints:

Primary endpoints:

* Tumour response at 3 months.
* Safety and toxicity profile of 166Ho-RE as adjuvant treatment after 177Lu-dotatate.

Secondary endpoints:

* Changes in tumour markers.
* Quality of Life (QoL).
* Biodistribution / Dosimetry.

Duration of treatment:

The study consists of a screening phase of approximately 2 weeks followed by a treatment phase of approximately 2-3 weeks. Patients will be followed until liver specific tumour progression or death has occurred, to a maximum of 12 months.

Methodology:

A first cohort of 30 patients will be treated with 166Ho-RE. After the first cohort, up to 3 additional cohorts of 6 patients will be treated with 166Ho-RE. The total number of patients treated in the HEPAR PLUS trial will therefore be at least 30 and at most 48 patients, depending on the observed number of responses. Early termination at a response interim analysis (after 30, 36 or 42 patients) is determined by pre-defined boundaries on the number of observed responses. The boundary in favour of treatment effect may be crossed before 30 patients are reached, but then the study will continue to at least 30 patients to allow estimation of the key secondary endpoints.

Number of study centers:

Single center (UMC Utrecht).

Adverse events:

All adverse events will be recorded throughout the study.

Inclusion period:

January 2014 - January 2017

Holmium-166-radioembolization in NET After Lutetium-177-dotatate; an Efficacy Study

Adjuvant Hepatic Holmium-166-radioembolization in Patients With Unresectable Liver Metastases of Neuroendocrine Origin, Who Have Been Treated With Lutetium-177-dotatate

To evaluate efficacy of adjuvant 166Ho-radioembolization (166Ho-RE) after systemic 177Lu-dotatate in a non-comparative phase II study

To evaluate QoL using EORTC questionnaire. The impact of treatment on QoL will be compared to tumour response, and other parameters. A questionnaire in the patient's native language will be provided.

To evaluate biodistribution using CT and quantitative SPECT.

To evaluate dosimetry using CT and quantitative SPECT. The imaging protocol after injection of 166Ho-PLLA-MS will consist of a dual isotope fusion SPECT/CT protocol.

To establish the safety and toxicity profile of treatment with 166Ho-microspheres as an adjuvant treatment after 177Lu-dotatate. This profile will be established using CTCAE (incl. SAE) methodology (CTCAE version 4.03).

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