Background: Neuroendocrine neoplasias (NENs) are characterised by the presence of somatostatin receptors (SSTR) on cell surface, in particular SSTR2. Somatostatin and its stable analogue (SSA) bind with high affinity to SSTR2. SSA can be radiolabelled, to both stage NENs using positron emission tomography (PET), and to deliver selective radiotherapy; peptide receptor radionuclide therapy (PRRT). PRRT consists of SSA linked to the long acting radionuclide. Radiolabelled SSA binds to SSTR2 and the complex is internalised delivering high dose radiation directly to the cancer. PRRT has been significantly improve survival outcomes and maintain quality of life in metastatic disease. Suitability for PRRT depends on presence of SSTR2 as determined by PET imaging, commonly with [⁶⁸Ga]-dotatate-PET. 20% of patients will have low or no uptake on [⁶⁸Ga]-dotatate-PET precluding PRRT. The upstream promoter region of SSRT2 is methylated, with percentage of methylation correlating with SSTR2 expression. We have shown that the use of the demethylating agent, guadecitabine, increases uptake on PET imaging in such that tumours previously negative on PET imaging, become positive, correlating with a dose dependent increase in tumoural SSTR2 expression. Combination guadecitabine and PRRT was well tolerated in vivo models of NETs. Overall aim was to utilise [⁶⁸Ga]-dotatate-PET as a biomarker of SSTR2 re-expression following treatment with the demethylating agent, ASTX727, such that patients previously unsuitable for PRRT can receive therapy, improving clinical outcome. 1) Utilise [⁶⁸Ga]-dotatate-PET to image epigenetic regulation of SSTR2 in response to ASTX727. 2) Evaluate clinical efficacy and safety of ASTX727 pre-treatment in combination with PRRT. 3) Explore impact on quality of life of combination therapy. Methods: 27 patients with no or equivocal uptake on [⁶⁸Ga]-dotatate-PET will be enrolled. [⁶⁸Ga]-dotatate-PET will be performed at baseline and after 8days of ASTX727 (oral, fixed dose 100mg cedazuridine + 35mg decitabine). If there is a significant increase in PET uptake, patients will receive combination ASTX727 and PRRT (Lutathera). Treatment will be repeated every 2months for 4 cycles. Response assessment (RECIST 1.1), tolerability and QoL will be assessed at start of each cycle. Tumour biopsies will be taken at baseline, and after cycle1 of ASTX727 (n=5), for SSTR2 methylation. Methylation will be correlated with PET uptake and outcome. LINE-1 methylation in peripheral blood monocytes will be assessed throughout. Current enrolment: 4. Clinical trial information: NCT05178693.