Intraperitoneal α-Emitting Radioimmunotherapy with ²¹¹At in Relapsed Ovarian Cancer: Long-Term Follow-up with Individual Absorbed Dose Estimations

Abstract

Eliminating microscopic residual disease with α-particle radiation is theoretically appealing. After extensive preclinical work with αparticle-emitting 211 At, we performed a phase I trial with intraperitoneal α-particle therapy in epithelial ovarian cancer using 211 At conjugated to MX35, the antigen-binding fragments-F(ab′) 2-of a mouse monoclonal antibody. We now present clinical outcome data and toxicity in a long-term follow-up with individual absorbed dose estimations. Methods: Twelve patients with relapsed epithelial ovarian cancer, achieving a second complete or nearly complete response with chemotherapy, received intraperitoneal treatment with escalating (20-215 MBq/L) activity concentrations of 211 At-MX35 F(ab′) 2. Results: The activity concentration was escalated to 215 MBq/L without any dose-limiting toxicities. Most toxicities were low-grade and likely related to the treatment procedure, not clearly linked to the α-particle irradiation, with no observed hematologic toxicity. One grade 3 fatigue and 1 grade 4 intestinal perforation during catheter implantation were observed. Four patients had a survival of more than 6 y, one of whom did not relapse. At progression, chemotherapy was given without signs of reduced tolerability. Overall median survival was 35 mo, with a 1-, 2-, 5-, and 10-y survival of 100%, 83%, 50%, and 25%, respectively. Calculations of the absorbed doses showed that a lower specific activity is associated with a lower single-cell dose, whereas a high specific activity may result in a lower central dose in microtumors. Individual differences in absorbed dose to possible microtumors were due to variations in administered activity and the specific activity. Conclusion: No apparent signs of radiation-induced toxicity or decreased tolerance to relapse therapy were observed. The dosimetric calculations show that further optimization is advisable to increase the efficacy and reduce possible long-term toxicity.

Targeted alpha therapy with astatine-211-labeled anti-PSCA A11 minibody shows antitumor efficacy in prostate cancer xenografts and bone microtumors

“…Among the α-emitters of interest for human use, 211 At is a main candidate and we have explored it continuously for clinical use in α-RIT of ovarian cancer [30][31][32]. Astatine-211 offers a theranostic approach to TAT since the decay involves the emission of K X-rays (77-93 keV) allowing for in vivo γ-quantification by planar and SPECT imaging.…”

Ovarian Cancer Targeted Theranostics

“…Intraperitoneal radioimmunotherapy using 212 Pb conjugated to trastuzumab, an α-emitter, in a first-inhuman study was found to be safe with patients showing a trend of decreasing tumor growth and blood-based biomarkers with increasing administered radioactivity (33). In another study Hallqvist et al, investigated intraperitoneal α-particle therapy using MX35, the antigen-binding fragments-F(ab ′ )2-of a mouse monoclonal antibody, conjugated with α-emitter 211 At in epithelial ovarian cancer patients (35). MX35 F(ab ′ )2 fragment targets the cell surface glycoprotein NaPi2b (SLC34A2) that is expressed on more than 90% of human epithelial ovarian cancers (74).…”

Radiolabelled Peptides for Positron Emission Tomography and Endoradiotherapy in Oncology

“…Since this clinical study, not many more reports were published. In 2009, one additional study reports on [ 211 At]At-MX35 F(ab') 2 for the treatment of ovarian cancer with a long-term follow-up presented most recently [62,63]. In contrast to Zalutsky et al, another group reported on 211 At-labelling via a direct procedure on an ε-lysyl-3-(trimethylstannyl)benzamide modified immunoconjugate [64].…”