First-in-human results of terbium-161 [161Tb]Tb-PSMA-I&T dual beta-Auger radioligand therapy in patients with metastatic castration-resistant prostate cancer (VIOLET): a single-centre, single-arm, phase 1/2 study
- PMID: 40617237
- DOI: 10.1016/S1470-2045(25)00332-8
First-in-human results of terbium-161 [161Tb]Tb-PSMA-I&T dual beta-Auger radioligand therapy in patients with metastatic castration-resistant prostate cancer (VIOLET): a single-centre, single-arm, phase 1/2 study
Abstract
Background: Terbium-161 (161Tb) emits beta-radiation similar to lutetium-177 (177Lu), with additional radiation over ultra-short path lengths from Auger electrons. 161Tb has shown superior in-vitro and in-vivo efficacy compared with 177Lu. We aimed to evaluate the safety of [161Tb]Tb-PSMA-I&T in patients with metastatic castration-resistant prostate cancer (mCRPC).
Methods: VIOLET was an investigator-initiated, single-centre, phase 1/2 trial, conducted at the Peter MacCallum Cancer Centre (Melbourne, VIC, Australia). Eligible patients were men aged 18 years or older with progressive mCRPC (histologically or cytologically confirmed adenocarcinoma of the prostate or unequivocal diagnosis of metastatic prostate cancer with an elevated serum prostate specific antigen) previously treated with an androgen receptor pathway inhibitor and taxane chemotherapy (unless medically unsuitable), Eastern Cooperative Oncology Group performance status of 0-2, and prostate-specific membrane antigen (PSMA) positivity (maximum standardised uptake value ≥20 on PSMA PET-CT) without discordance on 2-[18F]fluoro-2-deoxy-D-glucose (FDG) PET-CT. Dose escalation (3 + 3 design) had three prespecified radioactivities (4·4 GBq, 5·5 GBq, and 7·4 GBq). Up to six cycles of [161Tb]Tb-PSMA-I&T were administered intravenously every 6 weeks, reduced by 0·4 GBq for each cycle. Primary endpoints of phase 1 were dose-limiting toxicities, the maximum tolerated dose, and the recommended phase 2 dose, and the primary objective of phase 2 was evaluation of adverse events as defined by Common Terminology Criteria for Adverse Events version 5.0. We present here an interim analysis, with follow-up ongoing and recruitment reopened for an additional dose level (9·5 GBq). The trial is registered at ClinicalTrials.gov (NCT05521412).
Findings: Between Oct 14, 2022 and Feb 15, 2024, 30 eligible patients were enrolled. Median age was 69·0 years (IQR 66·0-74·8), screening PSA 26·9 ng/mL (10·1-70·0), PSMA mean standardised uptake value 8·2 (7·4-10·8), and 20 (67%) of 30 patients had received previous docetaxel. There were no dose-limiting toxicities. The maximum administered dose and recommended phase 2 dose was 7·4 GBq. Grade 3 treatment-related adverse events (TRAEs) were limited to pain (one [3%] of 30; the only serious TRAE) and lymphopenia (one [3%] of 30). No grade 4 TRAEs or treatment-related deaths occurred. No dose reductions or treatment discontinuation occurred for toxicity.
Interpretation: [161Tb]Tb-PSMA-I&T is safe at the maximum administered dose of 7·4 GBq. Further investigation of this promising radionuclide is warranted in larger, randomised clinical trials.
Funding: Prostate Cancer Foundation, Peter MacCallum Cancer Foundation, National Health and Medical Research Council Investigator Grant, Isotopia Molecular Imaging.
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Conflict of interest statement
Declarations of Interests JPB receives support from a Prostate Cancer Foundation Young Investigator Award and PhD support through an Australian Government Research Training Program Scholarship. LK received PhD support through an Australian Government Research Training Program Scholarship; and has received honoraria for speaker duties from AstraZeneca, Bayer, and Astellas, and fees from Bayer for participation in an Advisory Board. MSH receives research support and/or advisory board consulting fees to Peter MacCallum Cancer Centre from AdvanCell, ANSTO, Bayer, Isotopia, and Novartis, and consulting fees (personal) for lectures or advisory boards from Janssen, MSD, and Sanofi. DGM has received personal fees for consulting activities from Astellas, Bayer, Johnson & Johnson, Mundipharma, Cipla, and Novartis. AAA has consulted or served in an advisory role for Astellas Pharma, Novartis, Janssen, Sanofi, AstraZeneca, Pfizer, Bristol Myers Squibb, Tolmar, Telix Pharmaceuticals, Merck Sharpe & Dohme, Bayer, Ipsen, Merck Serono, Amgen, Noxopharma, Aculeus Therapeutics, and Daiichi Sankyo; participated in a speakers' bureau for Astellas Pharma, Novartis, Amgen, Bayer, Janssen, Ipsen, Bristol Myers Squibb, and Merck Serono; received travel funding from Astellas Pharma, Sanofi, Merck Serono, Amgen, Janssen, Tolmar, Pfizer, Bayer, and Hinova Pharmaceuticals; received honoraria from Janssen, Astellas Pharma, Novartis, Tolmar, Amgen, Pfizer, Bayer, Telix Pharmaceuticals, Bristol Myers Squibb, Merck Serono, AstraZeneca, Sanofi, Ipsen, Merck Sharpe & Dohme, Noxopharm, Aculeus Therapeutics, and Daiichi Sankyo; and received research funding (all institutional) from Astellas Pharma, Merck Serono, Novartis, Pfizer, Bristol Myers Squibb, Sanofi, AstraZeneca, GlaxoSmithKline, Aptevo Therapeutics, MedImmune, Bionomics, Synthorx, Astellas Pharma, Ipsen, Merck Serono, Lilly, Gilead Sciences, Exelixis, MSD, and Hinova Pharmaceuticals. SS is supported through a National Health and Medical Research Council (NHMRC) Investigator Grant; has consulted or served in an advisory role (all fees to institution) for AbbVie, AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Roche/Genentech, Janssen, AdvanCell, and Skyline Diagnostics; received research funding (all institutional) from Amgen, AstraZeneca, Merck Sharp and Dohme, Endocyte/Advanced Accelerator Applications, Genentech/Roche, Novartis, Pfizer, and Senhwa Biosciences; and has stock ownership in AdvanCell. LEM receives PhD support through an Australian Government Research Training Program Scholarship. LA has received speaker fees from Bristol Myers Squibb, Merck MSD, Eisai, Ipsen, and AstraZeneca; travel support from Roche Genentech; honoraria from Merck MSD and Eisai; and is supported by the Peter MacCallum Cancer Foundation Discovery Partner Fellowship. LF receives research support and/or advisory board consulting fees to Peter MacCallum Cancer Centre from Pimera, Isotopia, and Fusion Pharma. BT has received research support (all institutional) from Amgen, Astellas, AstraZeneca, Bayer, BMS, Ipsen, Janssen, MSD, Pfizer, and Roche; has received consulted or served on advisory board for Amgen, Astellas, AstraZeneca, Bayer, BMS, Ipsen, IQVIA, Janssen, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, and Tolmar; and has received honoraria from Amgen, Astellas, AstraZeneca, Bayer, BMS, Merck, and Pfizer. KEJ has received research support from an NHMRC postgraduate scholarship, and honoraria from the University of Western Ontario. JC has received honoraria from Bristol Myers Squibb. SEW has received travel support from the Medical Oncology Group of Australia, Australian and New Zealand Urogenital and Prostate Cancer Trials Group, and Astellas. GK received research support from Pfizer, ANSTO, and Cyclotek, and has a consulting and advisory role for ITM. WQH has received travel support from the Australian and New Zealand Urogenital and Prostate Cancer Trials Group and Roche. BE received honoraria from University of Western Ontario, and financial support from Australasian Association of Nuclear Medicine Specialists. All other authors declare no competing interests.
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