AACR 2023 | Phase I dose-escalation study of fractionated dose 225Ac J591 for mCRPC

So, we know that PSMA is a clinically validated target, and we have small molecules diagnostically in terms of PET scans, as well as a small molecule, that for therapy radiolabeled the beta emitter lutetium-177; that’s now approved and standard of care. There are also antibodies; actually, antibodies are a little bit older in terms of how long they’ve been in existence, and as we showed actually; last year at AACR, the uptake and retention of antibodies is actually; superior to small molecule. Small molecules work, and they’re great, but antibodies also have a place.

So, two separate presentations, one on conjugated antibodies, one with radiolabeled and one with a drug conjugate. In terms of antibodies, J591 has really been around the longest in terms of therapeutic development, really a couple of decades now. Initially radiolabeled with beta emitters, one of them was Lutetium-177, had some phase I dose escalation studies of a single dose, and actually, that single dose was presented with randomized data a couple of months ago at ASCO GU 2023, which delayed 18 month or improved 18-month metastasis-free survival in high-risk non-metastatic CRPC. But going back in drug development, we also looked at a fractionated dose which I think of as a kind of a dose-intense regimen where half of the dose is administered on day one and half the dose is administered two weeks later on day 15 of a single cycle. And separate trials, but looking at the overall data with that fractionation schedule, we’re able to give a higher amount of cumulative administered radioactivity with better tolerance overall in terms of myelosuppression and with the fractionated schedule, we can actually give it concurrent with docetaxel small phase I and that fractionated dose is actually now in Phase III trials not with us, but TLX has taken that over called TLX-591 in a phase III trial called ProstACT. So anyway, that’s the background. We know there’s also alpha emitters. Alpha emitters is kind of a high-level statement are more potent with a shorter range, and we can label antibodies as well as small molecules. So going back a couple of years, we did a Phase I single-dose trial, a dose escalation trial presented at ASCO 2021 that went up and up, and we did not hit an MTD. So, there was one DLT at a six-dose level at the seven-dose level had 0 to 6 and expanded and without patient selection and only one single PSMA selection with just the single dose, about two-thirds had some PSA decline, and about 40% had a PSA, 50% decline whether or not they were exposed to lutetian PSA in the past. So anyway, the follow-up study is we’re presenting one of the courts at ACR 2023, where we’re looking at a fractionated dose schedule just like we did with Lutetium-J591. And by the way, that fractionated schedule looks interesting with small molecule with lutetium-617. That’s a separate study. So, the overall study is now three cohorts; a fractionated dose with no prior lutetium exposure and, that’s what’s being presented now, a fractionated dose schedule with prior Lutetium exposure which is enrolling and a multiple dose schedule kind of the more common single dose every six weeks which is on hold right now.

So, in terms of what is presented at ACR 2023, dose-escalation study, PSMA PETs are done but not used for patient selection like we’ve normally done to assess that as a biomarker and went up to 65-kilo becquerels per kilogram at that dose level, so a total of 130. There were two DLTs of thrombocytopenia. One was a grade two thrombocytopenia. It was called the DLT because it delayed the subsequent dose by more than two weeks, and then one grade four. So, we took a step back, and what we’re now calling the recommended phase II dose is 60-kilo becquerels per kilogram times 2 or 120 total where there was one DLT out of six, but that’s the recommended phase two dose that we’re planning to take forward. So that really is the primary endpoint of the study as a phase I dose escalation. But there was interesting activity despite lack of PSMA selection. So, 95% had a PSA decline of any level, and 70% had a PSA 50, which I think is interesting for a pretreated patient population without PSMA selection. And that is going to move forward into phase II as soon as we get an amendment that we’re adding a patient-reported outcome tool called FACT-RNT, which was published earlier this year, in JAM, as well as dosimetry where we’re going to assess where some of the daughters go with SPECT and some imaging analysis technology. So as well, there’s a number of other studies that are going on with that particular compound combination, etc.