Phase I dose-escalation study of AlphaMedix for targeted-alpha-emitter therapy of PRRT-naive neuroendocrine patients.

4117 Background: Peptide-receptor-radioligand-therapy (PRRT) has been shown to increase the progression-free-survival (PFS) of neuroendocrine patients, however the objective response rate is rather low. The targeted-alpha-emitter therapy (TAT) of NETs can increase the ORR and induce partial or complete tumor response. In this abstract, we present results of the safety and efficacy of AlphaMedix ( 212 Pb-DOTAMTATE) done in PRRT-naïve patients with SSTR-expressing NETs (FDA IND 135150). Methods: The phase 1 dose escalation study (IND 135150) was designed according to a 3+3 dose-escalation scheme (30% increase of the dose in each subsequent cohort). We enrolled PRRT naïve subjects with biopsy-proven unresectable or metastatic SSTR-expressing NETs from different primary sites (midgut, rectal, pancreas, and lung) with at least one measurable lesion. Response to treatment was measured per RECIST 1.1 criteria and the effect on quality of life was measured with the EORTC-QLQ-C30 QOL questionnaire. Results: A total of 20 PRRT naïve subjects (10 men and 10 women; median age 60 ( range 27-80)) have been treated to date. 10 subjects in MAD4 cohort received at least three cycles of 212 Pb-DOTAMTATE at the highest dose level of 67.6 µCi/kg/cycle. Of these, 6/10 subjects (60%) have completed all four-cycles of treatment. Radiographic evaluation of these six-MAD4 patients reveal an ORR in 5 out of 6 subjects (83.3%) per RECIST 1.1 criteria (1CR, 4PR, 1SD) in addition to a 100% response according to 68 Ga-DOTATATE-PET/CT-imaging, defined as complete resolution of SSTR-positive lesions (CR) or Partial Response (PR) defined as resolution of most active lesions or substantially decreased SUV (>25%). No progression of disease was noted in the first six subjects enrolled in the MAD4 cohort who have completed treatment. All six-patients have 100% PFS up to 22 months (for the first 3-subjects in MAD4) and up to 19 months (next 3-patients). Except for mild-to-moderate, reversible hair loss, there were no other clinically significant drug related AE, or SAE. The most frequent AEs of any grade (> 4 subjects) reported include fatigue (35%), hyperglycemia (30%), lymphopenia (30%) alopecia (30%), and diarrhea (20%). Five grade 3 AEs were reported (back pain, dysarthria, dyspnea, acute kidney injury), no grade 4 AEs, and one grade 5 AE was reported. There was a significant improvement in the quality of life, reduction of pain, shortness of breath in the majority of subjects, with increase of energy. Conclusions: This F-I-H clinical study of AlphaMedix shows that PRRT with 212 Pb is feasible, well tolerated, and provides substantial reduction in tumor burden to patients with unresectable, metastatic SSTR-expressing NETs. Dramatic improvement in tumor burden and a positive impact on quality of life were seen in all of the PRRT naïve subjects who AlphaMedix at the highest dose tested. Clinical trial information: NCT03466216.