Background: PSMA is selectively overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression in other organs. PC is radiosensitive with dose-response data. Dose-fractionation may allow delivery of higher total doses with less radioresistance than doses several weeks to months apart. Small molecule PSMA inhibitor ligands can be successfully radiolabeled and have been used for imaging and treatment, but no dose-escalation study has been performed. Methods: Progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and docetaxel (or unfit/refuse chemo) without limit of # prior therapies provided adequate organ function, ECOG performance status 0-2, and without preselection for PSMA expression were enrolled. Treatment was a single cycle of fractionated dose 177Lu-PSMA-617 on D1 and D15 starting at 7.4 GBq with planned escalation up to 22.2 GBq in modified 3 + 3 dose-escalation. Primary endpoint is determination of dose limiting toxicity (DLT) and recommended phase 2 dose (RP2D) with secondary efficacy endpoints. Pre- and post-treatment 68Ga-PSMA11 PET/CT and post-treatment 177Lu-PSMA-617 imaging was performed in addition to standard serial CT and bone scans. Results: 29 men with median age 70 (range 56-87), median PSA 98.9 (range 6-2222) were treated. 93% with bone, 25% node, 14% lung, 7% liver, 7% other visceral metastases. 52% with at least 1 chemo, 45% >1 prior potent AR therapy, 17% with Ra223, 10 sip-T, 3% 177Lu-J591. No DLT was seen at any planned dose-level. With follow up ongoing, 41% with >50% PSA decline. Of 14 with paired CTC counts (CellSearch), 64% decreased, 14% stable, 14% increased (with 28.6% undetectable at 12 weeks). Adverse events include 55% xerostomia, 27.6% fatigue, 27.6% nausea, 27.6% thrombocytopenia, 20.7% anemia, 17.2% back pain. All had some PSMA uptake on imaging, with median (range) SUVmax 25 (4-119) bone, 32 (7-111) node, 10 (3-16) visceral. Conclusions: Dose-escalation of 177Lu-PSMA-617 is safe up to 22.2 GBq per cycle with fractionated dosing, with promising early efficacy and tolerability signals. Enrollment to the phase 2 study at RP2D will provide additional efficacy and toxicity data. Clinical trial identification: NCT03042468. Legal entity responsible for the study: Weill Cornell Medical College. Funding: Weill Cornell Medical College, Prostate Cancer Foundation, National Institutes of Health. Disclosure: All authors have declared no conflicts of interest.
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Tagawa et al. (2018) studied this question.