Pd01-11 Phase I Dose-Escalation Trial of Multiple and Fractionated-Dose Psma-Targeted Alpha Radionuclide (225ac-J591) for Metastatic Castration-Resistant Prostate Cancer

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) I (PD01)1 May 2024PD01-11 PHASE I DOSE-ESCALATION TRIAL OF MULTIPLE AND FRACTIONATED-DOSE PSMA-TARGETED ALPHA RADIONUCLIDE (225AC-J591) FOR METASTATIC CASTRATION-RESISTANT PROSTATE CANCER Michael Sun, Jones Nauseef, Andrés Ricaurte Fajardo, Zachary Davidson, Joseph Thomas, Samuel Ruder, Judith Stangl-Kremser, Sandra Huicochea Castellanos, Ana Molina, Cora Sternberg, Amie Patel, Sarah Yuan, Escarleth Fernandez, Edward Fung, Vasilios Avlonitis, Elisabeth O'Dwyer, David Nanus, Joseph Osborne, Neil Bander, and Scott Tagawa Michael SunMichael Sun , Jones NauseefJones Nauseef , Andrés Ricaurte FajardoAndrés Ricaurte Fajardo , Zachary DavidsonZachary Davidson , Joseph ThomasJoseph Thomas , Samuel RuderSamuel Ruder , Judith Stangl-KremserJudith Stangl-Kremser , Sandra Huicochea CastellanosSandra Huicochea Castellanos , Ana MolinaAna Molina , Cora SternbergCora Sternberg , Amie PatelAmie Patel , Sarah YuanSarah Yuan , Escarleth FernandezEscarleth Fernandez , Edward FungEdward Fung , Vasilios AvlonitisVasilios Avlonitis , Elisabeth O'DwyerElisabeth O'Dwyer , David NanusDavid Nanus , Joseph OsborneJoseph Osborne , Neil BanderNeil Bander , and Scott TagawaScott Tagawa View All Author Informationhttps://doi.org/10.1097/01.JU.0001009540.33579.43.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: PSMA targeted radionuclide therapy (TRT) involves either alpha (e.g. 225Ac) or beta (e.g. 177Lu) radionuclides conjugated to antibodies (e.g. J591) or small-molecule ligands (e.g. PSMA-617). Alpha-radionuclides deliver higher linear energy transfer with much shorter pathlength. In a first-in-human trial, a single-dose of 225Ac-J591 was safe, with no maximum tolerated dose reached, demonstrating preliminary efficacy. Subsequently, a parallel phase I/II dose-escalation study (NCT04506567) was developed exploring fractionated (FD) and multiple-dose (MD) regimens. METHODS: Eligibility: ECOG 0-2, intact organ function, progressive mCRPC after AR pathway inhibitor (ARPI) and taxane chemotherapy (or unfit/refuse). Prior Ra-223 and beta-TRT permitted initially. Baseline PSMA PET performed but not used for eligibility. In MD cohort, pts received 225Ac-J591 every 6 wks for up to 4 cycles; in FD cohort, single cycle of dose-dense therapy on D1 and D15. Primary objective was determination of dose-limiting toxicity (DLT). RESULTS: 18 pts treated in MD cohort (6 per level at 45, 55, 65 Kbq/kg/dose), 22 in FD cohort (45-65 KBq/kg/dose). Median age 72 (range 51-95), PSA 48.8 (0.67-2171.17). 21 (52.5%) CALGB high risk, 14 (35%) intermediate. 34 (85%) bone mets, 27 (67.5%) lymph node, 7 (17.5%) lung, 7 (17.5%) liver. 23 (57.5%) ≥2 ARPI, 32 (80%) ≥1 chemo, 16 (40%) sip-T, 6 (15%) Ra-223, 4 (10%) 177Lu-PSMA. Median SUVmax on PSMA PET 35.7 (3-130). In MD cohort, median # cycles 2 (range 1–4), cumulative radioactivity 130 KBq/kg (55-260) with 3 DLT at 65 KBq/kg (Gr1 and Gr2 thrombocytopenia TCP >2 wks, 1 Gr4 TCP), 2 DLT at 55 KBq/kg (1 Gr3 TCP >2 wks, 1 G4 TCP), 2 DLT at 45 KBq/kg (Gr1 and Gr2 TCP >2 wks). In FD cohort, 1 DLT at 65 KBq/kg (Gr2 TCP >2 wks) and 1 DLT at 60 KBq/kg (Gr4 TCP). In MD cohort, 13 (72%) with any PSA decline, 5 (28%) with PSA50; in FD cohort (21 evaluable), 20 (95%) with any PSA decline, 15 (71%) with PSA50. Of 27 with paired baseline and week 12 CTC count, 19 (70%) with CTC count decline/remain undetectable; 4 converted from unfavorable to favorable and 8 from detectable to undetectable. CONCLUSIONS: 225Ac-J591 administered in a dose-dense fractionated regimen appears safe with preliminary efficacy; ongoing study to optimize the regimen for 177Lu-PSMA exposed and naïve is in progress. 225Ac-J591 at multiple doses q6 weeks does not appear optimal given timing of blood count nadir, but in a separate study, 225Ac-J591 in combo with 177Lu-PSMA-I&T administered at 8-week intervals appears promising. Source of Funding: NIH, Weill Cornell Medicine © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e67 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Michael Sun More articles by this author Jones Nauseef More articles by this author Andrés Ricaurte Fajardo More articles by this author Zachary Davidson More articles by this author Joseph Thomas More articles by this author Samuel Ruder More articles by this author Judith Stangl-Kremser More articles by this author Sandra Huicochea Castellanos More articles by this author Ana Molina More articles by this author Cora Sternberg More articles by this author Amie Patel More articles by this author Sarah Yuan More articles by this author Escarleth Fernandez More articles by this author Edward Fung More articles by this author Vasilios Avlonitis More articles by this author Elisabeth O'Dwyer More articles by this author David Nanus More articles by this author Joseph Osborne More articles by this author Neil Bander More articles by this author Scott Tagawa More articles by this author Expand All Advertisement PDF downloadLoading ...