Evaluation of the tolerability and safety of [ 225 Ac]Ac-PSMA-I&T in patients with metastatic prostate cancer: a phase I dose escalation study

• Published in: BMC cancer Vol. 24; no. 1; p. 146
• Main Authors: Ling, Sui Wai, van der Veldt, Astrid A M, Konijnenberg, Mark, Segbers, Marcel, Hooijman, Eline, Bruchertseifer, Frank, Morgenstern, Alfred, de Blois, Erik, Brabander, Tessa
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 29.01.2024; BioMed Central
• Subjects: Abstinence; Androgens; Antiandrogens; Antimitotic agents; Antineoplastic agents; Cancer therapies; Care and treatment; Castration; Chemotherapy; Clinical trials; Deoxyribonucleic acid; Development and progression; Dipeptides - adverse effects; DNA; Dosage and administration; Dosimetry; Exocrine glands; FDA approval; Heterocyclic Compounds, 1-Ring; Humans; Immune system; Life span; Ligands; Male; Metastases; Metastasis; Patients; Pharmaceuticals; Prevention; Prospective Studies; Prostate cancer; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant - drug therapy; Radiation therapy; Radioisotopes; Radioisotopes - therapeutic use; Radiopharmaceuticals - adverse effects; Retrospective Studies; Risk factors; Safety; Study Protocol; Testing; Tomography; Toxicity; Treatment Outcome; Tumor cells; Germany; Actinium-225; Clinical protocol; Dose escalation; PSMA I&T; Prostate cancer
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-024-11900-y

Life expectancy of patients with metastatic castration-resistant prostate cancer (mCRPC) is still limited despite several systemic treatments. Within five years after diagnosis of primary prostate cancer, 10-20% of the patients have mCRPC and curation is not an option. Radionuclide therapy (RNT) targeted against prostate-specific membrane antigen (PSMA) emerged as a new treatment option and showed effective results in patients with mCRPC. Survival benefit after [ Lu]Lu-PSMA RNT has already been demonstrated in several clinical trials. However, [ Ac]Ac-PSMA ( Ac-PSMA) appears to be an even more promising radiopharmaceutical for the treatment of mCRPC. The use of alpha emitting radionuclides offers advantages over beta emitting radionuclides due to the high linear energy transfer effective for killing tumor cells and the limited range to reduce the radiation effects on the healthy tissue. However, these results are based on retrospective data and safety data of Ac-PSMA are still limited. Therefore, a prospective trial is needed to determine the optimal amount of activity that can be administered. The Ac-PSMA-Imaging & Therapy (I&T) trial is an investigator-initiated phase I, single-center, open label, repeated dose-escalation and expansion trial. Patient with PSMA-positive mCRPC after at least one line of chemotherapy and/or one line of nonsteroidal antiandrogen will be treated with Ac-PSMA-I&T in increasing amount of activity per cycle. Dose-escalation following an accelerated 3 + 3 design which allows to open the next dose-level cohort in the absence of dose limiting toxicity while the previous one is still ongoing. Up to 4 treatment cohorts will be explored including up to 3 dose-escalation cohorts and one expansion cohort where patients will be administered with the recommended dose. A total of up to 30 patients will be enrolled in this trial. All patients will be evaluated for safety. Additionally, dosimetry was performed for the patients in the dose-escalation cohorts after the first Ac-PSMA-I&T administration. This trial will assess the safety and tolerability of Ac-PSMA-I&T in patients with mCRPC to recommend the optimal dose for the phase II trial. ClinicalTrials.gov, (NCT05902247). Retrospectively registered 13 June 2023.