First clinical experience using targeted alpha-emitter therapy with 212Pb-DOTAMTATE (AlphaMedix TM) in patients with SSTR(+) neuroendocrine tumors.

559 Objectives: RadioMedix and Orano Med initiated the Phase 1, non-randomized, open-label, dose escalation study of 212Pb-octreotate (AlphaMedix™) in adult subjects with NETs overexpressing somatostatin receptors. The objectives of these studies are the determination of the safety, biodistribution, and preliminary effectiveness of this investigational drug. Methods: The 212Pb-octreotate treatment regimen was initiated using single intravenous (IV) administration of ascending doses (SAD cohort). Each cohort consisted of 3 subjects meeting the inclusion criteria of the protocol. There was an incremental 30% increase of the dose between each cohort. The SAD regimen was converted to a Multiple Ascending Dose (MAD) regimen which consists of 3 IV injections of drug administered at 8 (+/-1) week intervals. Subjects with histologically confirmed NETs and prior positive somatostatin analog scans, with no prior history of 177Lu/90Y/111In peptide receptor radionuclide therapy (PRRT), were enrolled in this study. The safety assessment included evaluation of the vital signs, laboratory tests, and ECG before and at multiple time points after the drug administration. These assessments were repeated through the follow-up phase of the study. The efficacy assessment was done based on the results of imaging studies (CT/MRI, 18F-FDG-PET/CT, Netspot®). The quality of life (QOL) was also monitored using ECOG performance status and the EORTC-QLQ-C30 QOL questionnaire. Results: Since the initiation of Phase I studies in February of 2018, we have enrolled 10 patients (6 females and 4 male) with SSTR expressing metastatic NETs. The treatments using single ascending dosing ( 6 patients) and the current level of the multi-ascending dosing were well-tolerated with the majority of AEs being Grade 1. Few mild adverse events reported during the follow-up visits ((2/9 patients experienced nausea and mild hair loss; 3/9 patients had abdominal pain and diarrhea, 2/9 patients had fatigue). There was no dose-limiting toxicity. To date, all patients have not shown cardiac toxicity by ECG or ECHO, or decrease in kidney function by GFR during follow-up visits. CT and MRI scans showed stable disease in all patients per RECIST 1.1. In addition, the decrease in SUVmax by PET/CT scans (18FDG and/or Netspot®) has been seen after 2 cycles of 212Pb-octreotate in the first MAD cohort. Conclusion:212Pb-octreotate therapy has shown a favorable safety profile at the current dose level. The full evaluation of the safety and clinical efficacy are still in progress. The high LET of decay products of 212Pb combined with the high SSTR-affinity of octreotate analog has the capacity to induce the irreversible damage of DNA in cancer cells and potentially improve the efficacy of this treatment over existing FDA approved options available for NETs patients. Funding Agency NCI SBIR Phase II Contract 2018 (PIID:HHSN261201800048C UPIID:75N91018C00048)