Phase I dose-escalation study of 225Ac-J591, a PSMA-targeting alpha-emitting antibody, in mCRPC
The first human test of an alpha-emitting radioactive drug attached to an antibody (rather than a small molecule) against PSMA found a safe dose in men with advanced prostate cancer who had exhausted other treatments, and shrank the PSA marker in nearly half of them - including those whose cancer had already stopped responding to the more common lutetium-177 PSMA treatment.
Overview
This first-in-human phase 1 dose-escalation trial tested 225Ac-J591 - the anti-PSMA monoclonal antibody J591 labelled with the alpha emitter actinium-225 - as a single intravenous dose in 32 men with progressive metastatic castration-resistant prostate cancer who had received or were ineligible for taxane chemotherapy and an androgen receptor pathway inhibitor. Unlike PSMA-617 or PSMA-I&T, J591 is a full antibody rather than a small peptidomimetic ligand, giving different pharmacokinetics (slower clearance, longer tumour residence). Patients were treated across seven dose levels (13.3 to 93.3 kBq/kg) without pre-selection by PSMA PET.
One dose-limiting toxicity (grade 4 anaemia and thrombocytopenia) occurred at 80 kBq/kg; none occurred at the highest dose level tested (93.3 kBq/kg), so a maximum tolerated dose was not reached and the recommended phase 2 dose was set at the top studied level. Most high-grade adverse events were haematological and dose-related; non-haematological toxicity was generally low grade - a different pattern from PSMA-617-based alpha agents, where xerostomia (dry mouth) from salivary gland uptake dominates, since antibodies clear the salivary glands less than small-molecule ligands. Efficacy signals were encouraging for a phase 1, dose-finding, unselected population: 46.9% of patients had a PSA decline of 50% or more at some point, 34.4% had a confirmed PSA50 response, and 59.1% had control of circulating tumour cells, with responses seen regardless of prior 177Lu-PSMA exposure.
As one of the first published clinical results for an antibody-based (rather than small-molecule) PSMA alpha-emitter, this trial supports antibody-delivered alpha therapy as a second route to targeted alpha therapy in prostate cancer, potentially with a different toxicity trade-off (more marrow suppression, less xerostomia) than PSMA-617-based agents, and without requiring PSMA PET pre-selection.
- Recommended phase 2 dose was the highest studied level, 93.3 kBq/kg; maximum tolerated dose was not reached across seven dose levels.
- One dose-limiting toxicity (grade 4 anaemia and thrombocytopenia) occurred, at 80 kBq/kg; none at the highest dose level.
- 46.9% of patients had a PSA decline of 50% or more at any time; 34.4% had a confirmed PSA50 response.
- Circulating tumour cell count control occurred in 13 of 22 evaluable patients (59.1%); responses were seen regardless of prior 177Lu-PSMA treatment.
- High-grade adverse events were predominantly haematological and radioactivity-dose related; non-haematological toxicity was generally low grade.
An alpha-emitting radioactive drug built on a PSMA-targeting antibody, rather than the small-molecule ligands used in existing PSMA therapies, was safe enough to move into further testing and shrank PSA in roughly a third to a half of heavily pre-treated men, including some whose cancer had already stopped responding to lutetium-177 PSMA therapy.
- Small, single-arm, phase 1 dose-escalation trial (32 patients) - not designed or powered to show a survival or definitive efficacy benefit.
- No PSMA PET pre-selection was used, unlike VISION and TheraP, so response rates are not directly comparable to those trials.
- Blood toxicity (anaemia, thrombocytopenia) tracked with dose, which will need careful management as the drug moves into larger trials.
Similar pages
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- CompanyFull-Life Technologies
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- IdeaAlpha-emitting PSMA therapy for oligometastatic (few-lesion) prostate cancer
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- TechnologyAlpha-emitter daughter redistribution ('free daughter' problem)
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- PairingDocetaxel (taxane chemotherapy) then 177Lu-PSMA-617
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