Phase Ib trial of reformulated niclosamide with abiraterone/prednisone in men with castration-resistant prostate cancer

Abstract Niclosamide has preclinical activity against a wide range of cancers. In prostate cancer, it inhibits androgen receptor variant 7 and synergizes with abiraterone. The approved niclosamide formulation has poor oral bioavailability. The primary objective of this phase Ib trial was to identify...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Mamta Parikh, Chengfei Liu, Chun-Yi Wu, Christopher P. Evans, Marc Dall’Era, Daniel Robles, Primo N. Lara, Neeraj Agarwal, Allen C. Gao, Chong-Xian Pan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7deaebe005d14169a2841537a9f695b8
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:7deaebe005d14169a2841537a9f695b8
record_format	dspace
spelling	oai:doaj.org-article:7deaebe005d14169a2841537a9f695b82021-12-02T11:39:27ZPhase Ib trial of reformulated niclosamide with abiraterone/prednisone in men with castration-resistant prostate cancer10.1038/s41598-021-85969-x2045-2322https://doaj.org/article/7deaebe005d14169a2841537a9f695b82021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85969-xhttps://doaj.org/toc/2045-2322Abstract Niclosamide has preclinical activity against a wide range of cancers. In prostate cancer, it inhibits androgen receptor variant 7 and synergizes with abiraterone. The approved niclosamide formulation has poor oral bioavailability. The primary objective of this phase Ib trial was to identify a maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of a novel reformulated orally-bioavailable niclosamide/PDMX1001 in combination with abiraterone and prednisone in men with castration-resistant prostate cancer (CRPC). Eligible patients had progressing CRPC, adequate end-organ function, and no prior treatment with abiraterone or ketoconazole. Patients were treated with escalating doses of niclosamide/PDMX1001 and standard doses of abiraterone and prednisone. Peak and trough niclosamide plasma levels were measured. Common Terminology Criteria for Adverse Events (CTCAE) v4.0 and Prostate Cancer Working Group 2 criteria were used to evaluate toxicities and responses. Nine patients with metastatic CRPC were accrued, with no dose-limiting toxicities observed at all dose levels. The recommended Phase II dose of niclosamide/PDMX1001 was 1200 mg orally (PO) three times daily plus abiraterone 1000 mg PO once daily and prednisone 5 mg PO twice daily. Trough and peak niclosamide concentrations exceeded the therapeutic threshold of > 0.2 µM. The combination was well tolerated with most frequent adverse effects of diarrhea. Five out of eight evaluable patients achieved a PSA response; two achieved undetectable PSA and radiographic response. A novel niclosamide/PDMX1001 reformulation achieved targeted plasma levels when combined with abiraterone and prednisone, and was well tolerated. Further study of niclosamide/PDMX1001 with this combination is warranted.Mamta ParikhChengfei LiuChun-Yi WuChristopher P. EvansMarc Dall’EraDaniel RoblesPrimo N. LaraNeeraj AgarwalAllen C. GaoChong-Xian PanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-7 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mamta Parikh Chengfei Liu Chun-Yi Wu Christopher P. Evans Marc Dall’Era Daniel Robles Primo N. Lara Neeraj Agarwal Allen C. Gao Chong-Xian Pan Phase Ib trial of reformulated niclosamide with abiraterone/prednisone in men with castration-resistant prostate cancer
description	Abstract Niclosamide has preclinical activity against a wide range of cancers. In prostate cancer, it inhibits androgen receptor variant 7 and synergizes with abiraterone. The approved niclosamide formulation has poor oral bioavailability. The primary objective of this phase Ib trial was to identify a maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of a novel reformulated orally-bioavailable niclosamide/PDMX1001 in combination with abiraterone and prednisone in men with castration-resistant prostate cancer (CRPC). Eligible patients had progressing CRPC, adequate end-organ function, and no prior treatment with abiraterone or ketoconazole. Patients were treated with escalating doses of niclosamide/PDMX1001 and standard doses of abiraterone and prednisone. Peak and trough niclosamide plasma levels were measured. Common Terminology Criteria for Adverse Events (CTCAE) v4.0 and Prostate Cancer Working Group 2 criteria were used to evaluate toxicities and responses. Nine patients with metastatic CRPC were accrued, with no dose-limiting toxicities observed at all dose levels. The recommended Phase II dose of niclosamide/PDMX1001 was 1200 mg orally (PO) three times daily plus abiraterone 1000 mg PO once daily and prednisone 5 mg PO twice daily. Trough and peak niclosamide concentrations exceeded the therapeutic threshold of > 0.2 µM. The combination was well tolerated with most frequent adverse effects of diarrhea. Five out of eight evaluable patients achieved a PSA response; two achieved undetectable PSA and radiographic response. A novel niclosamide/PDMX1001 reformulation achieved targeted plasma levels when combined with abiraterone and prednisone, and was well tolerated. Further study of niclosamide/PDMX1001 with this combination is warranted.
format	article
author	Mamta Parikh Chengfei Liu Chun-Yi Wu Christopher P. Evans Marc Dall’Era Daniel Robles Primo N. Lara Neeraj Agarwal Allen C. Gao Chong-Xian Pan
author_facet	Mamta Parikh Chengfei Liu Chun-Yi Wu Christopher P. Evans Marc Dall’Era Daniel Robles Primo N. Lara Neeraj Agarwal Allen C. Gao Chong-Xian Pan
author_sort	Mamta Parikh
title	Phase Ib trial of reformulated niclosamide with abiraterone/prednisone in men with castration-resistant prostate cancer
title_short	Phase Ib trial of reformulated niclosamide with abiraterone/prednisone in men with castration-resistant prostate cancer
title_full	Phase Ib trial of reformulated niclosamide with abiraterone/prednisone in men with castration-resistant prostate cancer
title_fullStr	Phase Ib trial of reformulated niclosamide with abiraterone/prednisone in men with castration-resistant prostate cancer
title_full_unstemmed	Phase Ib trial of reformulated niclosamide with abiraterone/prednisone in men with castration-resistant prostate cancer
title_sort	phase ib trial of reformulated niclosamide with abiraterone/prednisone in men with castration-resistant prostate cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/7deaebe005d14169a2841537a9f695b8
work_keys_str_mv	AT mamtaparikh phaseibtrialofreformulatedniclosamidewithabirateroneprednisoneinmenwithcastrationresistantprostatecancer AT chengfeiliu phaseibtrialofreformulatedniclosamidewithabirateroneprednisoneinmenwithcastrationresistantprostatecancer AT chunyiwu phaseibtrialofreformulatedniclosamidewithabirateroneprednisoneinmenwithcastrationresistantprostatecancer AT christopherpevans phaseibtrialofreformulatedniclosamidewithabirateroneprednisoneinmenwithcastrationresistantprostatecancer AT marcdallera phaseibtrialofreformulatedniclosamidewithabirateroneprednisoneinmenwithcastrationresistantprostatecancer AT danielrobles phaseibtrialofreformulatedniclosamidewithabirateroneprednisoneinmenwithcastrationresistantprostatecancer AT primonlara phaseibtrialofreformulatedniclosamidewithabirateroneprednisoneinmenwithcastrationresistantprostatecancer AT neerajagarwal phaseibtrialofreformulatedniclosamidewithabirateroneprednisoneinmenwithcastrationresistantprostatecancer AT allencgao phaseibtrialofreformulatedniclosamidewithabirateroneprednisoneinmenwithcastrationresistantprostatecancer AT chongxianpan phaseibtrialofreformulatedniclosamidewithabirateroneprednisoneinmenwithcastrationresistantprostatecancer
_version_	1718395709031448576

Phase Ib trial of reformulated niclosamide with abiraterone/prednisone in men with castration-resistant prostate cancer

Ejemplares similares