Cessation of Somatostatin Analogues After PRRT in Mid, Hind-Gut and Pancreatic Neuroendocrine Tumours

Inclusion Criteria:

• Adults over 18 years of age with well or moderately differentiated mid or hindgutneuroendocrine tumour, or pancreatic neuroendocrine tumour, metastatic andinoperable, demonstrating progression despite SSA treatment of sufficient diseasemagnitude to warrant PRRT as determined by the treating clinician and/or the NETMultidisciplinary Team (MDT).

• Must have measurable disease on triphasic CT/MRI as per RECIST 1.1.

• Ki67 ≤ 20% AND mitotic count 20 per HPF (i.e., WHO grade 1 or 2)

• Patient has been receiving growth-controlling doses of SSA for at least 12 weeksprior to study entry. This is a minimum of 30 mg Octreotide or120mg lanreotidemonthly.

• Uptake on SSTR PET scan demonstrating somatostatin receptor expression that issuitable for PRRT as judged by the clinical team. FDG PET scans are to be done atthe judgement of the treating team and are not required for enrolment into thisstudy.

• PRRT is deemed the most appropriate next treatment step (i.e., patient isinoperable, and liver directed therapies are not preferred)

• ECOG performance status 0 -2

• Written informed consent. Patients must be willing to either cease or continue SSA,depending on which study arm they are randomised to. Patients must be willing tocomply with all other study requirements

• Adequate renal, hepatic and haematologic function as judged by the treating team

• Life expectancy of at least 12 months

• Availability of tissue from resection or biopsy samples is desired but is notmandatory for study inclusion. Tissues will only be retrieved if the patientconsents to optional translational research sample collection. Similarly, bloods forresearch purposes will only be collected from those patients who consent to optionaltranslational research sample collection.

• Non-functioning NET: SSA treatment will have been commenced for control of tumourgrowth and not for carcinoid or other hormone overproduction syndrome, as judged bythe clinician and/or NET MDT. Non-functioning NET is judged by the treating clinicalteam based on patient symptomatology. In addition, for this study, non-functioningtumour is defined as:

• 24-hour urine 5-hydroxyindoleacetic acid (5HIAA) of <1.5x upper limit of normal (applies to mid and hind gut patients only).

• Please note: routine measurement of gastrin, insulin, C-peptide levels,glucagon etc. is not required unless clinically indicated.

• Never had escalation of the SSA treatment dose to control carcinoid carcinoidor other hormone-related symptoms

• Never required short acting SSA treatment to control carcinoid carcinoid orother hormone-related symptoms

• No significant carcinoid induced valvular heart disease IE: Echocardiogram tobe done in all patients within 26 weeks of study enrolment and deemed safe toproceed with PRRT by the treating team.

Exclusion Criteria:

• This study is for pancreatic, mid-gut and hind-gut NET only. Gastric and lung NETsare excluded

• Any patient on an SSA dose lower than the standard growth-control dose. Patientsmust have been on octreotide 30 mg or lanreotide 120 mg for at least 3 months priorto study entry.

• Prior chemotherapy or targeted therapy (e.g., everolimus). Patients who havereceived prior local therapy, including external beam radiotherapy and liverdirected therapy prior to or during SSA therapy are eligible.

• Any contraindication to PRRT, as per local institutional practice.

• Pregnancy. For female patients of childbearing potential and male patients with afemale partner who is of childbearing potential, contraception and counselling isrequired.

• Prior PRRT. Patients being considered for re-treatment with PRRT are not eligible

• Uncontrolled central nervous system metastases. Patients must have completed anysurgery or radiation at least 4 weeks prior to registration and must be offcorticosteroids for at least 2 weeks

• Any patient, in the opinion of the investigator, who will not comply with studyassessments and follow up visits. These might include any social, psychological, orgeographical concerns, including alcohol/drug abuse

• Any poorly controlled concurrent medical illness that may prevent the patient fromcomplying with study assessments and follow up. This is to be judged by the treatingteam

• Any concurrent or prior malignancy that, in the opinion of the treating team, mayinterfere with study assessments and endpoints