Project Grant R44CA265421

TARGETED ALPHA-EMITTER THERAPY OF PATIENTS WITH PRRT REFRACTORY NEUROENDOCRINE TUMORS - PROJECT SUMMARY A PEPTIDE RECEPTOR RADIONUCLIDE THERAPY (PRRT) USING BETA-EMITTER-LABELED SOMATOSTATIN ANALOGS HAS SHOWED INCREASE IN THE PROGRESSION-FREE-SURVIVAL (PFS) OF 177LU-DOTATATE TREATED SUBJECTS, HOWEVER THE OBJECTIVE RESPONSE RATE OF THIS GROUP IS RATHER LOW ONLY 18% COMPARE TO CONTROL GROUP. IN ADDITION, THE NUMBER OF COMPLETE RESPONSES AND PARTIAL RESPONSES SEEN IN THE DAILY CLINICAL PRACTICE IN LUTATHERA TREATED PATIENTS IS ALSO LOW. THIS IS DUE TO THE HETEROGENEITY OF NEUROENDOCRINE TUMORS; ADVANCED STAGE OF DISEASE AT THE TIME OF DIAGNOSIS; AND MORE IMPORTANTLY TUMOR RESISTANCE TO BETA-EMITTER PRRT DEVELOPED DURING THE THERAPY. THE TARGETED ALPHA- EMITTER THERAPY (TAT) OF NEUROENDOCRINE TUMORS CAN OVERCOME THESE LIMITATIONS AND OUR PHASE I DOSE ESCALATION STUDIES OF 212PB-DOTAMTATE (ALPHAMEDIX) PROVIDE CLINICAL EVIDENCE SUPPORTING THIS STATEMENT. OUR DOSE PHASE I STUDY DETERMINED SAFE AND HIGHLY EFFECTIVE DOSE OF ALPHAMEDIXTM IN PRRT NAIVE PATIENTS WITH METASTATIC NEUROENDOCRINE TUMORS REGARDLESS OF THE LOCATION OF THE PRIMARY TUMOR. ALL PATIENTS TREATED WITH THIS EFFECTIVE DOSE HAVE SHOWN THE OBJECTIVE RADIOLOGIC RESPONSE (ORR 83%) BY RECIST CRITERIA AND ALMOST COMPLETE RESPONSE BY NETSPOT PET/CT IMAGING. THE MAIN OBJECTIVE OF PROPOSED STUDY IS DETERMINATION OF THE SAFETY, PK, AND EFFICACY OF ALPHAMEDIX IN PRRT REFRACTORY PATIENTS WHO FAILED AND PROGRESSED AFTER LUTATHERA. THIS WILL BE ACCOMPLISHED DURING PHASE I CLINICAL STUDY (AMENDED IND 135150), FOLLOWED BY PHASE II STUDY (PROTOCOL NUMBER: RMX-ALPHA-R020). OBJECTIVE 1. PHASE I SAFETY, EFFICACY AND PK STUDIES OF THE EFFECTIVE DOSE OF ALPHAMEDIX IN PRRT-REFRACTORY PATIENTS REGARDLESS THE PRIMARY ORIGIN THE TUMOR. WITH SUCCESSFUL COMPLETION OF THIS OBJECTIVE, WE WILL CONFIRM THE EFFICACY AND SAFETY OF RECOMMENDED DOSES OF ALPHAMEDIX, COMPILE ALL MODULES FOR PHASE II CLINICAL STUDIES AND REQUEST TYPE B MEETING AND SUBMIT PHASE II CLINICAL PROTOCOL TO IRB AND FDA. OBJECTIVE 2. PHASE II NON-RANDOMIZED, OPEN-LABEL, MULTI-CENTER CLINICAL STUDIES OF ALPHAMEDIX IN PRRT REFRACTORY PATIENTS. WITH SUCCESSFUL COMPLETION OF THE OBJECTIVE, WE WILL DETERMINE THE MEDIAN PROGRESSION FREE SURVIVAL (MPFS) AND THE OVERALL SURVIVAL (OS) OF NETS PATIENTS, AS WELL AS THEIR TIME TO TUMOR PROGRESSION (TTP), AND SAFETY OF THE RECOMMENDED DOSES OF ALPHAMEDIX.