First-in-Human dose escalation of AlphaMedixTM for Targeted Alpha-Emitter Therapy of NETs

415 Introduction: Peptide Receptor Radioligand Therapy (PRRT) has been shown to be an effective treatment for patients with metastatic somatostatin receptor (SSTR) positive neuroendocrine tumors (NETs), however interest in developing alpha-emitter based therapies remains high. We present the initial safety and preliminary efficacy of this first-in-human (FIH) study of AlphaMedix™ (212Pb-DOTAMTATE), a novel somatostatin analog for Targeted Alpha-emitter Therapy (TAT), in patients with SSTR expressing NETs (FDA IND 135150). Methods: Thirteen adult subjects, 6 men and 7 women, median age 68 (range 27-75), with biopsy-proven unresectable or metastatic SSTR (+) NETs from different primary sites (small bowel, pancreas, and lung) with at least one measurable lesion were treated with a Single, weight-based, Ascending Dose (SAD) of AlphaMedix™. Dose escalation was conducted according to a classic 3+3 design. Once a partial response was observed in the SAD-3 cohort, the Multiple Ascending Dosing (MAD) began at the same dose level (3 cycles dosed every 8-weeks). Subjects who had previously received PRRT were excluded. All patients received amino acid renal protection prior to AlphaMedixTM administration. Response to treatment was measured per RECIST 1.1 and the effect on quality of life was measured with the EORTC-QLQ-C30 QOL questionnaire. Two SAD cohorts (SAD1 and SAD2) received 30.7 and 40.0 µCi/kg respectively. MAD3 received 52.0 µCi/kg per cycle and MAD4, began dosing at 67.6 µCi/ kg for a total dose ranging from 14.7 to 16.8 mCi, across 3 cycles. Results: All 3 subjects in MAD 4 who received 67.6 µCi/ kg for 3 cycles showed partial response with 73%, 71%, and 33% decrease in the size of the index lesions respectively. 68Ga DOTATATE PET/CT revealed almost a complete response in 2 subjects and a partial response in the third. No clinically significant investigational drug-related hematological and renal toxicity was noted. The most common adverse events noted were diarrhea 2/13(23%), nausea 4/13(30%), fatigue 4/13(30%), hyperglycemia 7/13(53%). Moderate hair loss was seen in 2/13 (15%) patients. Quality of life parameters suggest significant improvement in pain, energy, and shortness of breath in the majority of subjects. Conclusions: Dramatic decreases in tumor burden and a positive impact on quality of life were seen in all of the subjects who received three cycles of AlphaMedix at the highest dose tested. In addition, AlphaMedixTM was extremely well tolerated with only mild adverse events, most of which were attributable to the AA solution used for renal protection. This FIH study of AlphaMedixTM illustrates that PRRT with 212Pb is feasible, well-tolerated, and provides a substantial reduction in tumor burden to patients with unresectable, metastatic SSTR expressing NETs. Funding: This project was funded in part with Federal funds from National Cancer Institute, National Institute of Health and Human Services, under SBIR Phase II Contract No HHSN261201800048C.