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

Inclusion Criteria:

1. 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). See section 4.1 regarding the recording of thereason(s).

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

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

• Note: Participants are eligible if only a single proliferation index has beenperformed due to local institutional practice, provided that the results areconsistent with WHO grade 1 or 2 NET. However, if the results for both Ki67 andmitotic count are available, both results will need to be reported and are subjectto eligibility assessment.

4. 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-functioning tumour is defined as:

• Never had escalation of the SSA treatment dose to control carcinoid or otherhormone-related symptoms.

• Never required short acting SSA treatment to control carcinoid or otherhormone-related symptoms.

• For mid and hind gut (GI cohort) patients:

• 24-hour urine 5-hydroxyindoleacetic acid (5HIAA) <3x upper limit ofnormal.

• No significant carcinoid induced valvular heart disease. I.e.Echocardiogram to be within 12 weeks of study randomisation, and deemedsafe to proceed with PRRT by the treating team.

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

5. Patient has been receiving growth-controlling doses of SSA for at least 12 weeksprior to study enrolment, for example a minimum of 30mg Octreotide or 120mgLanreotide monthly. However, other SSA formulations used at growth-controlling dosesare also eligible.

6. 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.

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

8. ECOG performance status 0-2.

9. 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.

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

11. Life expectancy of at least 12 months.

Exclusion Criteria:

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

2. Any patient on an SSA dose lower than the standard growth-control dose. Patientsmust have been on an SSA equivalent to Octreotide 30mg or Lanreotide 120mg for atleast 3 months prior to study enrolment.

3. 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.

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

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

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

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

8. 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.

9. 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.

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