AlphaBet: Combination of Radium-223 and [ <sup>17</sup> <sup>7</sup>Lu]Lu-PSMA-I&amp;T in men with metastatic castration-resistant prostate cancer (clinical trial protocol)

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Abstract

Background

[ ¹⁷⁷Lu]Lu-PSMA is a radioligand therapy used in metastatic castration-resistant prostate cancer (mCRPC). Despite a survival benefit, the responses for many patients receiving [ ¹⁷⁷Lu]Lu-PSMA are not durable, and all patients eventually develop progressive disease. The bone marrow is the most common site of progression. Micrometastases in this area likely receive an inadequate dose of radiation, as the emitted beta-particles from ¹⁷⁷Lu travel an average range of 0.7 mm in soft tissue, well beyond the diameter of micrometastases. Radium-223 ( ²²³Ra) is a calcium-mimetic and alpha-emitting radionuclide approved for use in men with mCRPC with bone metastases. The range of emitted alpha particles in soft tissue is much shorter (≤100 μm) with high linear energy transfer, likely more lethal for osseous micrometastases. We anticipate that combining a bone-specific alpha-emitter with [ ¹⁷⁷Lu]Lu-PSMA will improve eradication of micrometastatic osseous disease, and thereby lead to higher and longer responses.

Methods

This is a single-center, single-arm phase I/II trial evaluating the combination of ²²³Ra and [ ¹⁷⁷Lu]Lu-PSMA-I&T in men with mCRPC. Thirty-six patients will receive 7.4 GBq of [ ¹⁷⁷Lu]Lu-PSMA-I&T, concurrently with ²²³Ra in escalating doses (28 kBq/kg – 55kBq/kg), both given intravenously every six weeks for up to six cycles. Eligible patients will have at least two untreated bone metastases visible on bone scintigraphy, and PSMA-positive disease on PSMA PET scan. Patients must have adequate bone marrow and organ function and be willing to undergo tumor biopsies. Patients with discordant disease visible on FDG PET scan (defined as FDG positive disease with minimal or no PSMA expression and no uptake on bone scan) will be excluded. Other key exclusion criteria include the presence of diffuse marrow disease, prior treatment with ²²³Ra or [ ¹⁷⁷Lu]Lu-PSMA, or more than one prior line of chemotherapy for prostate cancer. The co-primary objectives of this study are to determine the maximum tolerated dose of ²²³Ra when combined with [ ¹⁷⁷Lu]Lu-PSMA-I&T and the 50% PSA response rate.

Conclusion

The AlphaBet trial is a phase I/II study combining ²²³Ra with [ ¹⁷⁷Lu]Lu-PSMA-I&T in patients with mCRPC. We aim to enroll the first patient in Q3 2022, and recruitment is anticipated to continue for 24 months.

Study registration

NCT05383079.

Related collections

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Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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Author and article information

Contributors

Louise Kostos: URI : http://loop.frontiersin.org/people/1893207/overview

Jing Xie: URI : http://loop.frontiersin.org/people/2083106/overview

Luc Furic: URI : http://loop.frontiersin.org/people/1073478/overview

Arun A. Azad: URI : http://loop.frontiersin.org/people/1713542/overview

Michael S. Hofman: URI : http://loop.frontiersin.org/people/128537/overview

Journal

Journal ID (nlm-ta): Front Med (Lausanne)

Journal ID (iso-abbrev): Front Med (Lausanne)

Journal ID (publisher-id): Front. Med.

Title: Frontiers in Medicine

Publisher: Frontiers Media S.A.

ISSN (Electronic): 2296-858X

Publication date (Electronic): 18 November 2022

Publication date Collection: 2022

Volume: 9

Electronic Location Identifier: 1059122

Affiliations

[1] ¹Department of Medical Oncology, Peter MacCallum Cancer Centre , Melbourne, VIC, Australia

[2] ²Sir Peter MacCallum Department of Oncology, University of Melbourne , Melbourne, VIC, Australia

[3] ³Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre , Melbourne, VIC, Australia

[4] ⁴Prostate Cancer Theranostics and Imaging Centre of Excellence, Peter MacCallum Cancer Centre , Melbourne, VIC, Australia

[5] ⁵Centre for Biostatistics and Clinical Trials (BaCT), Peter MacCallum Cancer Centre , Melbourne, VIC, Australia

[6] ⁶Department of Cancer Imaging, Peter MacCallum Cancer Centre , Melbourne, VIC, Australia

[7] ⁷Cancer Evolution and Metastasis Program, Peter MacCallum Cancer Centre , Melbourne, VIC, Australia

[8] ⁸Cancer Research Division, Peter MacCallum Cancer Centre , Melbourne, VIC, Australia

Author notes

Edited by: Roy Larsen, Sciencons AS, Norway

Reviewed by: Laura Evangelista, University of Padua, Italy; Caroline Stokke, Oslo University Hospital, Norway

*Correspondence: Michael S. Hofman Michael.Hofman@ 123456petermac.org

Arun A. Azad Arun.Azad@ 123456petermac.org

This article was submitted to Nuclear Medicine, a section of the journal Frontiers in Medicine

†These authors share senior authorship

Article

DOI: 10.3389/fmed.2022.1059122

PMC ID: 9716623

PubMed ID: 36465905

SO-VID: fa6b6af6-45d7-4d4a-80fb-d2fc805955cd

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 30 September 2022

Date accepted : 03 November 2022

Page count

Figures: 2, Tables: 4, Equations: 0, References: 32, Pages: 13, Words: 8202

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