Capecitabine ON Temozolomide Radionuclide Therapy Octreotate Lutetium-177 NeuroEndocrine Tumours Study

Inclusion Criteria:

* Adults ≥18 years old with histologically proven, moderate to well-differentiated G1/2 pancreatic or midgut NETs with Ki-67 \< 20%;
* The presence of somatostatin receptor avidity suitable for PRRT demonstrated on 68Ga-octreotate PET scan;
* Progressive advanced/metastatic disease that has progressed during or after ≤ 2 prior systemic therapies;
* Unresectable disease, determined by an appropriately specialized surgeon or deemed not suitable for liver directed therapies where liver is the only site of disease;
* ECOG performance status 0-2;
* Ability to swallow oral medication;
* Adequate renal function (measured creatinine clearance \> 50 ml/min by DTPA or 51CR-EDTA), bone marrow function (Hb \> 9 g/d/L, ANC \> 1.5 x109L, and platelets \> 100 x 10/L);
* Adequate liver function (serum total bilirubin ≤ 1.5 x ULN, and Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver metastases)). INR ≤ 1.5 (or on a stable dose of LMW heparin for \>2 weeks at time of enrolment .);
* Life expectancy of at least 9 months;
* Study treatment both planned and able to start within 28 days of randomisation; )
* Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments;
* Signed, written informed consent.

Exclusion Criteria:

* Primary NETs other than small bowel (midgut) or pancreatic NETs;
* Cytotoxic chemotherapy, targeted therapy, or biotherapy within the last four weeks;
* Prior intrahepatic 90Y microspheres, such as SIR-Spheres in the past six months;
* Prior Peptide Receptor Radionuclide Therapy;
* Major surgery/surgical therapy for any cause within one month;
* Surgical therapy of loco-regional metastases within the last three months prior to randomisation;
* Uncontrolled metastatic disease to the central nervous system. To be eligible, CNS metastases should have been treated with surgery and/or radiotherapy and the patient should have been receiving a stable dose of steroids for at least 2 weeks prior to randomisation, with no deterioration in neurological symptoms during this time;
* Poorly controlled concurrent medical illness. E.g. unstable diabetes (Note: optimal glycaemic control should be achieved before starting trial therapy); Symptomatic NYHA class III or IV congestive cardiac failure, myocardial infarction within 6 months of start of the study, serious uncontrolled cardiac arrhythmia, unstable angina, or any other clinically significant cardiac disease;
* History of other malignancies within 5 years except where treated with curative intent AND with no current evidence of disease AND considered not to be at risk of future recurrence Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder are eligible;
* Any uncontrolled known active infection, including chronic active hepatitis B, hepatitis C, or HIV. Testing for these is not mandatory unless clinically indicated. Participants with known Hepatitis B/C infection will be allowed to participate providing evidence of viral suppression has been documented and the patient remains on appropriate anti-viral therapy;
* Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of capecitabine/temozolomide (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or substantial small bowel resection);
* Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse;
* Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men must have been surgically sterilised or use a (double if required) barrier method of contraception .