Pilot Study of Hyperfractionated Dosing of Lutetium-177–Labeled Antiprostate-Specific Membrane Antigen Monoclonal Antibody J591 (177Lu-J591) for Metastatic Castration-Resistant Prostate Cancer

Abstract

Lessons Learned Hyperfractionation of lutetium‐177 (177Lu)‐J591 for patients with metastatic castration‐resistant prostate cancer did not appear to have any additional advantage over the single dose 177Lu‐J591 or fractionated two‐dose 177Lu‐J591 therapy. Definite conclusions were challenging because of the small sample size of this study, and so further studies are needed to evaluate the viability of the hypothesis. On the basis of available data, a registration study of 177Lu‐J591 (also known as TLX591) is planned and will use the two‐dose fractionation schedule (Telix Pharma Q3 2019 update https://telixpharma.com/news-media/). Background Phase I and II single‐dose studies of lutetium‐177 (177Lu)‐J591, a radio‐labeled antibody binding prostate‐specific membrane antigen (PSMA), demonstrated safety and efficacy with dose response. Modest dose fractionation of 177Lu‐J591 (2 doses) has less myelosuppression per similar cumulative dose, allowing higher doses to be administered safely. We hypothesized that additional dose fractionation would allow a higher cumulative dose, potentially with less toxicity and more efficacy. Methods Men with progressive metastatic castration‐resistant prostate cancer and adequate organ function were enrolled. 177Lu‐J591 was administered at 25 mCi/m2 every 2 weeks until the emergence of related grade 2 toxicity. 177Lu‐J591 imaging was performed and circulating tumor cell (CTC) counts were measured before and after treatment along with standard monitoring. Results Six subjects in a single cohort, with a median age of 68.6 years, were enrolled. Patients received three to six doses (cumulative 75−150 mCi/m2). Two (33%) patients had >30% prostate‐specific antigen (PSA) decline and three (50%) had CTC count decline. Two (33%) experienced grade (Gr) 4 neutropenia (without fever), three (50%) had Gr 4 thrombocytopenia (without hemorrhage), and two (33%) required platelet transfusions. Following hematological improvement, two patients developed worsening cytopenia during prostate cancer progression; bone marrow biopsies revealed infiltrative tumor replacing normal marrow elements without myelodysplasia. Targeting of known disease sites was seen on planar imaging in all. Conclusion Hyperfractionation of 177Lu‐J591 is feasible but does not seem to have significant advantages over the two‐dose fractionation regimen.

Imaging expression of prostate‐specific membrane antigen and response to PSMA‐targeted β‐emitting radionuclide therapies in metastatic castration‐resistant prostate cancer

“…We performed a post hoc analysis of all subjects who were included in our phase I/II β‐radiation emitting PSMA‐TRT studies with enrollment during the period between July 2002 and October 2018 1–4,6,7 . Key eligibility criteria included prospective mCRPC by Prostate Cancer Working Group criteria with no available standard therapies or refusal of standard therapies and intact performance status and organ function as previously described.…”

“…With respect to radionuclide activity for pretreatment imaging, 5 mCi of 111 In were used. As 177 Lu is a therapeutic radionuclide with both β and γ emission, other than those that were imaged with 111 In or 68 Ga, there was no pretreatment imaging specifically using 177 Lu; rather images used for initial treatment served as baseline imaging 1–4,6,7 …”

“…To measure PSMA uptake we used semiquantitative imaging with a five‐point imaging score as previously described 3,4,6,7 . Imaging scores (IS) were assigned based upon PSMA uptake in tumors compared to liver uptake and scored by two independent radiologists on a 0–4 scale (Table ).…”

“…PSMA‐targeted radionuclide therapy (TRT) is a promising therapeutic approach for mCRPC. We and others have performed a series of phase I and II studies utilizing antibodies or small molecule ligands conjugated with β‐emitting radionuclides including lutetium 177 ( 177 Lu) and yttrium 90 ( 90 Y) 1–8 . These sequential studies have demonstrated the safety and activity of PSMA‐TRT 1–8 as well as a dose–response relationship 3,4,6 …”

Review of Lutetium-177-labeled Anti-prostate-specific Membrane Antigen Monoclonal Antibody J591 for the Treatment of Metastatic Castration-resistant Prostate Cancer

“…After phase I and II single-dose studies of 177 Lu-J591 demonstrated safety and efficacy with dose-response, and dose fractionation of 177 Lu-J591 permitted higher cumulative dose administration with less myelosuppression per similar cumulative dose in single-dose studies, the idea of the hyperfractionation of 177 Lu-J591 emerged [8][9][11][12][13]. The researchers hypothesized that the hyperfractionation of 177 Lu-J591 will allow the safer administration of a higher cumulative dose with less potential toxicity.…”