This is a phase I dose escalation study of fractionated dose-intense actinium-225-J591 in metastatic castration resistant prostate cancer. This drug is a PSMA-targeted radiotherapy; the J591 represents a monoclonal antibody that we developed at Cornell that has now been conjugated to a potent alpha emitter called actinium-225.
What was the study design?
For this phase I dose escalation study we used a modified 3+3 dose escalation study. We initially started with three cohorts and in dose escalation added a fourth cohort of intermediate dosage to determine, as our primary objectives, our dose limiting toxicity and our recommended phase II dose.
I’d like to discuss in brief our inclusion criteria. These patients all had metastatic CRPC based on Prostate Cancer Working Group 3, had adequate performance status of 0 to 2 by ECOG and had all received at least one AR pathway inhibitor. Similarly, all patients were mandated to have prior exposure to taxane chemotherapies excepting those patients who may have been ineligible or refusing.
In this cohort patients who had received PSMA radioligand therapy previously were excluded. Of note, this was a study amendment so two patients included in these data had had prior exposure to PSMA radioligand therapy. Adequate organ function was also required and key exclusion criteria included prior receipt of non-PSMA beta emitters and any known history of myelodysplastic syndrome.
What were the key findings?
With 225Ac-J591, in this phase I dose escalation study, patients were treated with two doses, one in cycle 1 on cycle day 15. The primary objective was to determine the dose limiting toxicity, the DLT, and the recommended phase II dose. Before we get into the results, I think it’s important to discuss how we defined the DLT. Our DLT period was the eight weeks following the first dose and the DLT was defined in that period of any patient who had grade 4 thrombocytopenia or grade 3 with major bleeding, grade 4 neutropenia or any incidence of febrile neutropenia and any grade 3 or worse non-haematologic toxicity. Finally, relevant to the study design, any grade 2 or worse adverse event attributable to the drug that delayed receipt of the second dose by greater than two weeks.
As the primary objective was DLT and recommended phase II dose, in keeping with phase I studies the main goal is safety. We observed at the highest dose, dose cohort 3, two DLTs – a patient with grade 4 thrombocytopenia, I will note that this patient did have prior exposure to PSMA radioligand therapy, and a grade 2 thrombocytopenia that resulted in delay to the second dose by two weeks. Consequently, a fourth cohort of intermediate dose of 120kBq/kg was added and at this intermediate dose six patients were treated in keeping with the 3+3 design and only one DLT was observed. This patient had grade 4 thrombocytopenia that was transient; the patient’s thrombocytopenia has resolved and his platelet count is normal today. From this we chose as a recommended phase II dose 120kBq/kg.
In this phase I study we also have preliminary evidence for efficacy and this is represented both by PSA changes and CTC changes. Of the patients, the 23 patients, evaluable for PSA change, 22, or nearly all patients, had any PSA decline with frequent best declines of 50% and 90%, including in 26% of patients. Of those patients with a 50% or better decline, 12 of the 16 are confirmed PSA 50s and one of the remaining four patients is awaiting his confirmed PSA response.
We also had CTC responses. Of 14 patients evaluable at baseline at 12 weeks for CTC counts, or circulating tumour cell counts, we saw responses of any type in 79% of patients. Half of patients experienced a change from detectable to undetectable and two of five patients who were unfavourable at baseline converted to favourable.
To go back to the AEs just for a bit, for haematologic AEs we did observe, as mentioned, some grade 3, grade 4 neutropenia and thrombocytopenia. In the non-haematologic toxicities we observed no high grade toxicity, so no grade 3 or grade 4 non-haematologic toxicities. Among the most common non-haematologic toxicities which were grade 1 and grade 2 were fatigue and pain flare.
How can these results impact future trials in prostate cancer?
These results are important for our expansion into the phase II which we will do at the recommended phase II dose of 120kBq/kg. Another important addition in the phase II is the addition of a radioligand therapy specific patient reported outcome called FACT-RNT. This will focus on the symptoms and side effects and patients’ experiences that might be unique or different receiving a drug like a radionuclide therapy as opposed to conventional chemotherapy or targeted drugs. The second is the introduction of dosimetry, this is using multi-time-point spec to measure dose received rather than dose administered.
Additionally, more broadly for 225Ac-J591, we have other ongoing studies in the phase I setting. One is for patients who have mandated to have had prior lutetium-177 radioligand therapy. This is particularly relevant, given the FDA approval of PSMA-617 conjugated to lutetium-177.
We also have combination studies, so the same drug, 225Ac-J591, in combination with a lutetium conjugated small molecule ligand called PSMA-INT and also a randomised phase II study where every patient will be receiving ARSI and pembrolizumab in the pre-chemo setting for metastatic CRPC and will be randomised to receive or not receive one dose of 225Ac-J591.
More broadly speaking, now that PSMA radio-targeted therapy is part of the FDA approval, we will be moving these drugs earlier and earlier in the treatment. So rather than being always heavily pre-treated, later stage, later line metastatic CRPC, we think there is real potential for these drugs, including with an alpha emitter like actinium, in earlier stage patient care.