In vivo Evaluation of [225Ac]Ac-DOTAZOL for α-Therapy of Bone Metastases

Pfannkuchen, Nina; Bausbacher, Nicole; Pektor, Stefanie; Miederer, Matthias; Rösch, Frank

doi:10.2174/1874471011666180604083911

Cited by 23 publications

(18 citation statements)

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“…Subsequently, zoledronate received regulatory approval for the prevention of SREs and treating bone metastases. The labelling of zoledronate to beta- and alpha-emitting radionuclides like 177 Lu and 225 Ac, respectively, was a logical development [ 19 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

[177Lu]Lu-DOTA-ZOL bone pain palliation in patients with skeletal metastases from various cancers: efficacy and safety results

et al. 2020

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Background [177Lu]Lu-DOTA-ZOL has shown promising results from the dosimetry and preclinical aspects, but data on its role in the clinical efficacy are limited. The objective of this study is to evaluate the efficacy and safety of [177Lu]Lu-DOTA-ZOL as a bone pain palliation agent in patients experiencing pain due to skeletal metastases from various cancers. Methods In total, 40 patients experiencing bone pain due to skeletal metastases were enrolled in this study. The patients were treated with a mean cumulative dose of 2.1 ± 0.6 GBq (1.3–2.7 GBq) [177Lu]Lu-DOTA-ZOL in a median follow-up duration of 10 months (IQR 8–14 months). The primary outcome endpoint was response assessment according to the visual analogue score (VAS). Secondary endpoints included analgesic score (AS), global pain assessment score, Eastern Cooperative Oncology Group Assessment performance status (ECOG), Karnofsky performance status, overall survival, and safety assessment by the National Cancer Institute’s Common Toxicity Criteria V5.0. Results In total, 40 patients (15 males and 25 females) with a mean age of 46.6 ± 15.08 years (range 24–78 years) were treated with either 1 (N = 15) or 2 (N = 25) cycles of [177Lu]Lu-DOTA-ZOL. According to the VAS response assessment criteria, complete, partial, and minimal responses were observed in 11 (27.5%), 20 (50%), and 5 patients (12.5%), respectively with an overall response rate of 90%. Global pain assessment criteria revealed complete, partial, minimal, and no response in 2 (5%), 25 (62.5%), 9 (22.5%), and 4 (10%) patients, respectively. Twenty-eight patients died and the estimated median overall survival was 13 months (95% CI 10–14 months). A significant improvement was observed in the VAS, AS, and ECOG status when compared to baseline. None of the patients experienced grade III/IV haematological, kidney, or hepatotoxicity due to [177Lu]Lu-DOTA-ZOL therapy. Conclusion [177Lu]Lu-DOTA-ZOL shows promising results and is an effective radiopharmaceutical in the treatment of bone pain due to skeletal metastases from various cancers.

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Section: Discussionmentioning

confidence: 99%

[177Lu]Lu-DOTA-ZOL bone pain palliation in patients with skeletal metastases from various cancers: efficacy and safety results

et al. 2020

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“…Subsequently, zoledronate received regulatory approval for the prevention of SREs and treating bone metastases. The labelling of zoledronate to beta and alpha-emitting radionuclides like 177 Lu and 225 Ac, respectively, were a logical development [19,20].…”

Section: Discussionmentioning

confidence: 99%

“…For bone pain palliation it has been labelled with several bisphosphonates such as ethylene diamine tetramethylene phosphonic acid (EDTMP) [7 -9], (4-{[(bis(phosphonomethyl)) carbamoyl]methyl}-7,10-bi (carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid (BPAMD) [10][11][12][13][14][15] Zoledronate (DOTA-ZOL) [16][17][18][19][20][21][22], and DOTMP [23,24]. Zoledronic acid, compared to EDTMP and DOTMP, has signi cantly higher hydroxyapatite binding and better internalization by osteoclasts.…”

Section: Introductionmentioning

confidence: 99%

[177Lu]Lu-DOTA-ZOL Bone Pain Palliation in Patients with Skeletal Metastases From Various Cancers: Efficacy and Safety Results

Yadav

Ballal

Meckel

et al. 2020

Preprint

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Background: [177Lu]Lu-DOTA-ZOL has shown promising results from the dosimetry and preclinical aspects, but data on its role in the clinical efficacy is limited. In this light, the objective of this study is to evaluate the efficacy and safety of [177Lu]Lu-DOTA-ZOL as a bone pain palliation agent in patients experiencing pain due to skeletal metastases from various cancers. Methods: 40 patients experiencing bone pain due to skeletal metastases were enrolled in this study. The patients were treated with a mean cumulative dose of 2.1 ± 0.6 GBq (1.3 - 2.7 GBq) [177Lu]Lu-DOTA-ZOL in a median follow-up duration of 10 months (IQR: 8 - 14 months). The primary outcome endpoint was response assessment according to the visual analog score (VAS). Secondary endpoints included analgesic score (AS), global pain assessment score, Eastern Cooperative Oncology Group Assessment performance status (ECOG), Karnofsky Performance Status (KPS), overall survival, and safety assessment by the National Cancer Institute’s Common Toxicity Criteria V5.0. Results: 40 patients, 15 males, and 25 females with a mean age of 46.6 ± 15.08 years (range: 24 - 78 years) were treated with either 1 (N=15) or 2 (N= 2lobal5) cycles of [177Lu]Lu-DOTA-ZOL. g According to the VAS response assessment criteria, complete, partial, and minimal responses were observed in 11 (27.5%), 20 (50%), and 5 patients (12.5%), respectively with an overall response rate of 90%. Global pain assessment criteria revealed complete, partial, minimal and no response in 2 (5%), 25 (62.5%), 9 (22.5%), and 4 (10%) patients, respectively. Twenty eight patients died and the estimated median overall survival was 13 months (95% CI: 10 - 14 months). A significant improvement was observed in the VAS, AS and ECOG status when compared to baseline. None of the patients experienced grade III/IV hematological, kidney or hepatotoxicity due to [177Lu]Lu-DOTA-ZOL therapy. Conclusion: [177Lu]Lu-DOTA-ZOL shows promising results and is an effective radiopharmaceutical in the treatment of bone pain due to skeletal metastases from various cancers.

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“…Alpha particles are characterized by high LET and short travel distances; therefore, PSMA-targeted alpha therapies may cause potent and local cytotoxicity to PSMA-expressing cells [3, 4]. Alpha-labeled bisphosphonates, such as 225 Ac-EDTMP or 225 Ac-zolendronate, may also be considered as they accumulate in the bone microenvironment of osteoblastic lesions [112, 113].…”

Section: Psma—an Emerging and Promising Target For Pc Therapymentioning

confidence: 99%

Advances in targeted alpha therapy for prostate cancer

et al. 2019

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Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment.

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In vivo Evaluation of [²²⁵Ac]Ac-DOTA^ZOL for α-Therapy of Bone Metastases

Abstract: [225Ac]Ac-DOTAZOL repeats the well-known pharmacology of DOTAZOL derivatives in preclinical evaluations. It thus may be considered for translational application together with strategies to reduce renal toxicity.

Cited by 23 publications

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[177Lu]Lu-DOTA-ZOL bone pain palliation in patients with skeletal metastases from various cancers: efficacy and safety results

[177Lu]Lu-DOTA-ZOL bone pain palliation in patients with skeletal metastases from various cancers: efficacy and safety results

[177Lu]Lu-DOTA-ZOL Bone Pain Palliation in Patients with Skeletal Metastases From Various Cancers: Efficacy and Safety Results

Advances in targeted alpha therapy for prostate cancer

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