A phase IB and randomised phase IIA trial of CApecitabine plus Radium-223 (Xofigo™) in breast cancer patients with BONe metastases: CARBON trial results

Winter, M.C.; Coleman, Rob; Kendall, Jessica; Palmieri, Carlo; Twelves, Chris; Howell, Sacha J.; Macpherson, Iain; Wilson, Caroline; Purohit, Kash; Gath, Jacqui; Taylor, Christine L.; Eastell, Richard; Murden, Geraldine; Brown, Sarah; Rathbone, Emma; Brown, Janet

doi:10.1016/j.jbo.2022.100442

Cited by 7 publications

(9 citation statements)

References 12 publications

(12 reference statements)

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“…Ra-223 has been used for breast cancer patients with bone-dominant disease with osteoblastic and osteolytic lesions ( 85 – 87 ). Coleman et al have demonstrated that 223 Ra targeted osteoblastic, but not osteolytic lesions, in breast cancer patients with bone-dominant disease ( 85 ).…”

Section: Stromal Manipulations: From Osteolytic To Osteoblasticmentioning

confidence: 99%

“…Coleman et al have demonstrated that 223 Ra targeted osteoblastic, but not osteolytic lesions, in breast cancer patients with bone-dominant disease ( 85 ). The results are not surprising because the balance between osteoblastic and osteolytic lesions have not been taken into account ( 87 ). However, these studies have demonstrated that 223 Ra is safe ( 85 – 87 ), with the potential to be combined with other therapies after pretreatment with bisphosphonates and denosumab.…”

Section: Stromal Manipulations: From Osteolytic To Osteoblasticmentioning

confidence: 99%

“…The results are not surprising because the balance between osteoblastic and osteolytic lesions have not been taken into account ( 87 ). However, these studies have demonstrated that 223 Ra is safe ( 85 – 87 ), with the potential to be combined with other therapies after pretreatment with bisphosphonates and denosumab.…”

Section: Stromal Manipulations: From Osteolytic To Osteoblasticmentioning

confidence: 99%

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Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach

Juzeniene

Stenberg²,

Bruland³

et al. 2023

Front. Med.

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Metastases are the primary cause of death among cancer patients and efficacious new treatments are sorely needed. Targeted alpha-emitting radiopharmaceuticals that are highly cytotoxic may fulfill this critical need. The focus of this paper is to describe and explore a novel technology that may improve the therapeutic effect of targeted alpha therapy by combining two radionuclides from the same decay chain in the same solution. We hypothesize that the dual targeting solution containing bone-seeking 224Ra and cell-directed complexes of progeny 212Pb is a promising approach to treat metastatic cancers with bone and soft tissue lesions as well as skeletal metastases of mixed lytic/osteoblastic nature. A novel liquid 224Ra/212Pb-generator for rapid preparation of a dual targeting solution is described. Cancer cell targeting monoclonal antibodies, their fragments, synthetic proteins or peptides can all be radiolabeled with 212Pb in the 224Ra-solution in transient equilibrium with daughter nuclides. Thus, 224Ra targets stromal elements in sclerotic bone metastases and 212Pb-chelated-conjugate targets tumor cells of metastatic prostate cancer or osteosarcoma. The dual targeting solution may also be explored to treat metastatic breast cancer or multiple myeloma after manipulation of bone metastases to a more osteoblastic phenotype by the use of bisphosphonates, denosumab, bortezomib or hormone therapy prior to treatment. This may improve targeting of bone-seeking 224Ra and render an augmented radiation dose deposited within metastases. Our preliminary preclinical studies provide conceptual evidence that the dual 224Ra-solution with bone or tumor-targeted delivery of 212Pb has potential to inhibit cancer metastases without significant toxicity. In some settings, the use of a booster dose of purified 212Pb-conjugate alone could be required to elevate the effect of this tumor cell directed component, if needed, e.g., in a fractionated treatment regimen, where the dual targeting solution will act as maintenance treatment.

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Section: Stromal Manipulations: From Osteolytic To Osteoblasticmentioning

confidence: 99%

Section: Stromal Manipulations: From Osteolytic To Osteoblasticmentioning

confidence: 99%

Section: Stromal Manipulations: From Osteolytic To Osteoblasticmentioning

confidence: 99%

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Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach

Juzeniene

Stenberg²,

Bruland³

et al. 2023

Front. Med.

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“…Клеточная линия ACHN была субкультивирована для наращивания необходимого количества клеток. Субкультивирование производили в культуральных флаконах с площадью поверхности 25 см 2 . Первоначально полученные монослои клеток снимали из культурального флакона, используя диссоциирующую смесь трипсин 0,25% : версен 0,02% (АО «ПанЭко») в соотношении 1:2-1:3.…”

Section: исследования фармакокинетики рфлп при выборе модели патологи...unclassified

“…С другой стороны, без транспортной молекулы, которая отвечает за адресную доставку препарата, реализация его диагностического или терапевтического действия невозможна. Исключением являются растворы радионуклидов, обладающих органной специфичностью (например, йодид натрия, 131 I [1], или хлорид радия, 223 Ra [2]). Иными словами, характер распределения РФЛП в живом организме определяется свойствами векторной молекулы и/или химическими свойствами радионуклида.…”

Section: Introductionunclassified

Pharmacokinetic Studies of Radiopharmaceuticals

Lunev

Luneva

Klementyeva

2022

Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo pr

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Особенности изучения радиофармацевтических лекарственных препаратов (РФЛП) определяются малыми концентрациями используемой фармацевтической субстанции. Методы, применяемые при изучении препаратов, не содержащих радионуклиды, не могут быть использованы при изучении РФЛП. Задачи изучения поведения РФЛП могут быть решены с помощью радионуклидных методов. Цель работы: сравнительная характеристика подходов к доклиническому изучению фармакокинетики РФЛП и других лекарственных средств. В статье рассмотрены основные аспекты проведения фармакокинетических исследований препаратов, содержащих и не содержащих радионуклиды, определены сходства и различия в проведении фармакокинетических исследований. Приведены примеры собственных фармакокинетических исследований РФЛП: возможность использования РФЛП «Золедроновая кислота, 99m Tc» для визуализации костных патологий у пациентов, получающих препарат Зомета®; доказательство преимущества моделирования ортотопического ксенографта по сравнению с гетеротопическим. Сделан вывод о том, что методы, основанные на ионизирующем излучении, имеют неоспоримые преимущества перед другими методами, используемыми для описания фармакокинетики лекарственных препаратов (к примеру, возможность детекции нано-и/или пикоколичества фармацевтической субстанции неинвазивными методами). Данные фармакокинетических исследований могут быть использованы для характеристики как безопасности, так и функциональной пригодности радиофармпрепаратов.

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Radium-223 in women with hormone receptor-positive bone-metastatic breast cancer receiving endocrine therapy: pooled analysis of two international, phase 2, randomized, double-blind, placebo-controlled trials

Rugo,

Van Poznak,

Neven

et al. 2023

Breast Cancer Res Treat

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Background Most women with advanced breast cancer have skeletal metastases. Radium-223 is an alpha-emitting radionuclide that selectively targets areas of bone metastases. Methods Two double-blind, placebo-controlled studies of radium-223 were conducted in women with hormone receptor-positive (HR+), bone-predominant metastatic breast cancer. All patients received endocrine therapy (ET), as a single agent of the investigator’s choice (Study A) or exemestane + everolimus (Study B). Patients were randomized to receive radium-223 (55 kBq/kg) or placebo intravenously every 4 weeks for six doses. Accrual was halted following unblinded interim analyses per protocol amendments, and both studies were terminated. We report pooled analyses of symptomatic skeletal event-free survival (SSE-FS; primary endpoint), radiologic progression-free survival (rPFS) and overall survival (OS; secondary), and time to bone alkaline phosphatase (ALP) progression (exploratory). Results In total, 382 patients were enrolled, and 196 SSE-FS events (70% planned total) were recorded. Hazard ratios (95% confidence intervals) and nominal p values for radium-223 + ET versus placebo + ET were: SSE-FS 0.809 (0.610–1.072), p = 0.1389; rPFS 0.956 (0.759–1.205), p = 0.7039; OS 0.889 (0.660–1.199), p = 0.4410; and time to bone ALP progression 0.593 (0.379–0.926), p = 0.0195. Radium-223- or placebo-related treatment-emergent adverse events were reported in 50.3% versus 35.1% of patients (grade 3/4: 25.7% vs. 8.5%), with fractures/bone-associated events in 23.5% versus 23.9%. Conclusions In patients with HR+ bone-metastatic breast cancer, numeric differences favoring radium-223 + ET over placebo + ET for the primary SSE-FS endpoint were suggestive of efficacy, in line with the primary outcome measure used in the underlying phase 2 studies. No similar evidence of efficacy was observed for secondary progression or survival endpoints. Adverse events were more frequent with radium-223 + ET versus placebo + ET, but the safety profile of the combination was consistent with the safety profiles of the component drugs. Clinical trial registration numbers Study A: NCT02258464, registered October 7, 2014. Study B: NCT02258451, registered October 7, 2014.

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A phase IB and randomised phase IIA trial of CApecitabine plus Radium-223 (Xofigo™) in breast cancer patients with BONe metastases: CARBON trial results

Cited by 7 publications

References 12 publications

Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach

Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach

Pharmacokinetic Studies of Radiopharmaceuticals

Radium-223 in women with hormone receptor-positive bone-metastatic breast cancer receiving endocrine therapy: pooled analysis of two international, phase 2, randomized, double-blind, placebo-controlled trials

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