Dose-escalation results of a phase I study of 225Ac-J591 for progressive metastatic castration resistant prostate cancer (mCRPC).
Scott T. Tagawa, Joseph R. Osborne, Muhammad Junaid Niaz, Shankar Vallabhajosula, Panagiotis J. Vlachostergios, Charlene Thomas, Ana M. Molina, Cora N. Sternberg, Sharon Singh, Escarleth Fernandez, John W. Babich, David M. Nanus, Karla V. Ballman, Neil H. Bander
Abstract
114 Background: Prostate-specific membrane antigen (PSMA) can be targeted by antibodies (Ab) or small molecule ligands labeled with potent α emitters (e.g. 225 Ac). Unlike ligands, Ab biodistribution does not include non-tumor organs such as the salivary glands, kidneys and small bowel. We performed a phase I single ascending dose Ab study. Methods: Eligibility: progressive mCRPC following at least 1 potent AR pathway inhibitor (ARPI; e.g. abi/enza) and docetaxel (or unfit/refuse chemo) without limit of # prior therapies provided adequate organ function. Baseline 68 Ga-PSMA11 PET was performed but not used for eligibility. Single-subject cohorts received a single infusion of 225 Ac-J591 until grade (Gr) > 1 attributable toxicity or dose level 5, then transition to 3+3 design. Cohort 1 = 13.3 KBq/kg with planned escalation up to dose level 7 (93.3 KBq/kg). Dose-limiting toxicity (DLT) defined as attributable Gr 4 heme or Gr 3/4 non-heme toxicity. Results: 22 men were treated on 7 dose levels; median age 72.5 (range 58-89), PSA 146.5 (4.8-7168.4); 82% with >2 prior ARPI, 64% chemo, 45% sipuleucel-T, 23% radium-223, 55% prior 177 Lu-PSMA. By standard imaging 82% bone, 36% lymph node, 9% liver mets. At the time of data cutoff, 1 of 6 men in cohort 6 (80 KBq/kg) had DLT (Gr 4 anemia and platelets); he had 4 prior cycles of 177 Lu-PSMA. No other attributable Gr >2 non-hematologic or Gr >3 heme AE (including 0 of 6 at the highest dose level). Low Gr temporary AE’s include: 16 (73%) with fatigue, 11 (50%) pain, 11 (50%) nausea, 6 (27%) with xerostomia (5 of 6 with prior 177 Lu-PSMA), 3 (14%) AST elevation. With follow-up ongoing, 60% with any PSA decline, 35% with >50% PSA decline. Of 10 with detectable baseline and 12-week CTC counts (CellSearch), 8 declined (45-100% decline); 5 (50%) with CTC count conversion. While PSMA uptake was not a prerequisite for treatment, all had some PSMA uptake on 68 Ga-PSMA11 PET/CT; 64% with SUV max >5x liver SUV, 14% 2.5x – 5x liver, and 23% with SUV max 0-2.5x liver SUV. Conclusions: PSMA-targeted alpha-emitter 225 Ac utilizing intact Ab J591 is well tolerated with early evidence of clinical activity in a pre-treated population, including the majority with prior 177 Lu-PSMA. Clinical trial information: NCT03276572.