TheraSphere Selective Internal Radiation Therapy (SIRT) as Treatment for Neuroendocrine Tumours With Liver Mets

Study Overview
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Brief Summary
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This is an open label study for patients with inoperable metastatic neuroendocrine liver deposits to see whether treatment with Selective Internal Radiation Therapy (TheraSpheres) could lead to improved treatment response rates with acceptable toxicity (minimal serious adverse events reported). This research will also look at the progression free survival and quality of life of the patients who decide to join the study.

Detailed Description
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Neuroendocrine tumours (NETs) are tumours which arise from cells of the neuroendocrine system, which is the mechanism by which the hypothalamus maintains homeostasis. Neuroendocrine cells secrete hormones, a type of signalling molecule, that play a role in many of the body's different processes including growth and development. Surgical resection remains the only curative approach to NETs. However, due to non-specific representations, over 50% of NETs are unresectable at diagnosis. Patients with metastatic high grade, poorly differentiated tumours have a median overall survival of 5 months, as compared to 33 months for those with metastatic low or intermediate grade, well differentiated disease. The liver is the most common site for metastasis and is directly correlated to a much poorer prognosis if moderately to poorly differentiated disease is seen, with 5-year survival of 50% less than those without liver metastases. Current treatment for non-resectable NETs include somatostatin analogues, systematic anti-cancer therapy (with etoposide/carboplatin being the most commonly prescribed regime), radionuclide therapy, Meta-iodobenzylguanidine Therapy (MiBGG) and Peptide Related Radiation Therapy (PRRT). The last showing great promise in clinical trials with progression free survival at 20 months of 65.2% in the Netter1 trial. However, this therapy is reliant on tumoural expression and a key density of the somatostatin 2 receptor (SSTR2), a feature that is often lost with increasing grade and aggressiveness of disease. In short, the current proposed treatments for non-resectable NETs are still to be optimised and depend heavily on patient status, SSTR2 expression and in the case of chemotherapy, is based on evidence of treatment regimens for other types of cancer. Selective Internal Radiation Therapy (SIRT), by hepatic arterial delivery of yttrium-90 (Y-90) labelled microspheres, is a safe and effective locoregional therapy that combines a dual anticancer therapy, combining the effects of hepatic arterial embolization with targeted delivery of high dose radiation. This selectively delivers a tumouricidal dose of beta-radiation to the liver tumour, while maintaining a low radiation dose to surrounding normal tissue. 20% of the blood supply of healthy liver comes from the hepatic artery, while 90% of liver tumours derive >90% of their blood supply from the same artery and so the hepatic artery is therefore a compelling target to deliver largely tumour specific treatment, sparing healthy liver. SIRT microspheres are also small enough to get trapped in the liver microvasculature but too large to pass through capillary beds and should therefore not reach other places of the body to cause unwanted side effects. TheraSpheres consist of an yttrium-90 containing glass microsphere. Yttrium-90 is a pure beta emitter with a half-life of approximately 64.1 hours. It has the same toxicity profile as many chemotherapy agents with the common side effects reported as fatigue, anorexia, pain, nausea and vomiting. In a past clinical trial on NETs, SIRT has shown a radiological response rate of 63% and a median survival of 70 months.

Official Title
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A Phase II Assessment of the Safety and Efficacy of TheraSphere® Selective Internal Radiation Therapy (SIRT) in the Treatment of Metastatic (Liver) Neuroendocrine Tumours (NETs)

Conditions
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Neuroendocrine Tumors, Liver Metastases

Intervention / Treatment
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* Radiation: TheraSpheres Selective Internal Radiation Therapy (SIRT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients must be discussed at a specialist hepatobiliary multi-disciplinary team meeting (MDT) and meet the following criteria: Histologically confirmed neuroendocrine tumour, with documented grade. >18 years of age Patients may be on SSAs concurrently.Patients must have had at least one previous line of therapy Unresectable liver only or liver predominant metastases (typically involving >25% but <60% of the liver, and technically inoperable, or unfeasible secondary to medical comorbidity) Have measurable disease by RECIST 1.1 criteria Life expectancy of >12 weeks Eastern Cooperative Oncology Group (ECOG) / World Health Organisation (WHO) Performance Status of 0-1 Adequate liver function (bilirubin less than 34 umol/L in the absence of a reversible cause) Blood work: patients must have Platelet count of > or = to 50x10^9/L Hb of > or = to 8.5g/dL Alanine Aminotransferase (ALT) and Aspartate transaminase (AST) < 5 x Upper limit of normal (ULN) Serum creatinine < 1.5 x ULN Internal Normalised Ration (INR) < 2.0 Patients with portal vein thrombosis may be considered, as determined at MDT (A compromised main portal vein as demonstrated on triple-phase CT scan unless selective or super-selective SIRT can be performed and the other safety criteria are fulfilled) Exclusion Criteria: Patients who meet any of the following exclusion criteria will NOT be considered eligible for this study. Clinically apparent ascites or other signs of hepatic failure on physical examination Severe uncontrollable coagulopathy No safe vascular access to the liver, as determined by triple phase CT Potential for excess radiation exposure (>30Gy) to the lungs, as determined by pretreatment 99mTc-MAA lung shunt (>20% shunt) Shunting to the GI tract that cannot be corrected by embolization, as demonstrated by hepatic angiogram Previous Transarterial chemoembolization (TACE) or SIRT Multiple biliary stents, or ongoing cholangitis, or any intervention for, or compromise of, the Ampulla of Vater Previous external bean radiotherapy to the liver Systemic anti-cancer therapy within the last 4 weeks (excluding 1st line therapy with SSA) Treatment with Vascular endothelial growth factor (VEGF) inhibitors within 3 months prior to therapy Previous or concurrent cancer, other than Basal Cell Carcinoma, unless treated curatively 5 or more years prior to entry Tumour involvement of >60% of the liver Oesophageal bleeding during the last 3 months Any history of hepatic encephalopathy Transjugular intrahepatic portosystemic shunt (TIPS) Must not be at risk of hepatic or renal failure Contraindications against angiography Pregnancy and breast feeding. Women of child-bearing potential must have a negative pregnancy test 14 days before treatment, and at the time of theresphere administration. Subjects with another significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with completion of the study. Must not be participating in concurrent clinical trials evaluating treatment intervention(s).

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TheraSpheres Selective Internal Radiation Therapy (SIRT)<br>Radiation therapy | Radiation: TheraSpheres Selective Internal Radiation Therapy (SIRT)<br>* Single-photon emission computed tomography (SPECT) imaging will assess 99mTc-MAA (MAA being macro aggregated albumin) deposition in the tumour bed to estimate the dose of radiation to tumour and healthy tissue, before administration of TheraSpheres to eligible patients<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Record incidence of adverse events overall and by severity, as well as serious adverse events using the National Cancer Institute - Common Toxicity Criteria (NCI-CTC) for Adverse Events, version 4.03 (CTCAE V4.03) | Throughout study completion, up to 1 year | 
| Define objective response rate (ORR) | This is the best overall response (CR+PR) determined by RECIST 1.1 | Throughout study completion, up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Determined by RECIST 1.1 and defined as date of treatment to the date of first documentation of disease progression | Throughout study completion, up to 1 year | 
| Overall survival | Date of randomisation to the date of death from any cause, or censored at date of last contact | Throughout study completion, up to 1 year | 
| Quality of life | Evaluated using the European Organisation for Research and Treatment of Cancer (EORTC) questionnaires QLQ-C30 (Quality of Life Questionnaire type C30) at baseline, week 8 and 3 monthly thereafter | Throughout study completion, up to 1 year | 
| Quality of life 2 | - Evaluated using the European Organisation for Research and Treatment of Cancer (EORTC) questionnaires QLQ-I.NET21 (Quality of Life Questionnaire, type I.Neuroendocrine Tumour number 21) at baseline, week 8 and 3 monthly thereafter | Throughout study completion, up to 1 year |