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Pharmacokinetics and safety of ixazomib plus lenalidomide–dexamethasone in Asian patients with relapsed/refractory myeloma: a phase 1 study
BACKGROUND: The oral proteasome inhibitor ixazomib is under phase 3 clinical investigation in multiple myeloma (MM) in combination with lenalidomide–dexamethasone. This study was conducted to investigate the pharmacokinetic and safety profiles of ixazomib, administered with lenalidomide–dexamethason...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559079/ https://www.ncbi.nlm.nih.gov/pubmed/26337806 http://dx.doi.org/10.1186/s13045-015-0198-1 |
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author | Gupta, Neeraj Goh, Yeow Tee Min, Chang-Ki Lee, Jae Hoon Kim, Kihyun Wong, Raymond S. M. Chim, Chor Sang Hanley, Michael J. Yang, Huyuan Venkatakrishnan, Karthik Hui, Ai-Min Esseltine, Dixie-Lee Chng, Wee Joo |
author_facet | Gupta, Neeraj Goh, Yeow Tee Min, Chang-Ki Lee, Jae Hoon Kim, Kihyun Wong, Raymond S. M. Chim, Chor Sang Hanley, Michael J. Yang, Huyuan Venkatakrishnan, Karthik Hui, Ai-Min Esseltine, Dixie-Lee Chng, Wee Joo |
author_sort | Gupta, Neeraj |
collection | PubMed |
description | BACKGROUND: The oral proteasome inhibitor ixazomib is under phase 3 clinical investigation in multiple myeloma (MM) in combination with lenalidomide–dexamethasone. This study was conducted to investigate the pharmacokinetic and safety profiles of ixazomib, administered with lenalidomide–dexamethasone, in East Asian patients with relapsed/refractory MM. METHODS: Adult patients with measurable disease who had received 1–3 prior lines of therapy received oral ixazomib on days 1, 8, and 15, lenalidomide (25 mg) on days 1–21, and dexamethasone (40 mg) on days 1, 8, 15, and 22, in 28-day cycles. Primary objectives were to characterize ixazomib plasma pharmacokinetics, determine the recommended phase 2/3 dose, and evaluate safety and tolerability. RESULTS: Forty-three patients were enrolled. No dose-limiting toxicities were reported for the first six patients receiving ixazomib (4.0 mg), confirming this as the recommended phase 2/3 dose. Ixazomib was rapidly absorbed with a median T(max) of 1.5 h on day 1 and 2.0 h on day 15 of cycle 1 and had a geometric mean terminal half-life of 6.1 days. Twenty-one (49 %) patients had at least one drug-related grade ≥3 adverse event (AE); the most common were neutropenia (19 %), diarrhea (14 %), and thrombocytopenia (12 %). Twenty-eight of 43 (65 %) response-evaluable patients had at least a partial response. The recommended phase 2/3 dose for ixazomib was determined to be 4.0 mg. CONCLUSIONS: The all-oral combination of ixazomib plus lenalidomide–dexamethasone appeared active and well tolerated at 4.0 mg. Consequently, East Asian patients enrolled in phase 3 studies are receiving the same ixazomib dose as patients in other regions. TRIAL REGISTRATION: This study is registered at NCT01645930. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13045-015-0198-1) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4559079 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-45590792015-09-04 Pharmacokinetics and safety of ixazomib plus lenalidomide–dexamethasone in Asian patients with relapsed/refractory myeloma: a phase 1 study Gupta, Neeraj Goh, Yeow Tee Min, Chang-Ki Lee, Jae Hoon Kim, Kihyun Wong, Raymond S. M. Chim, Chor Sang Hanley, Michael J. Yang, Huyuan Venkatakrishnan, Karthik Hui, Ai-Min Esseltine, Dixie-Lee Chng, Wee Joo J Hematol Oncol Research Article BACKGROUND: The oral proteasome inhibitor ixazomib is under phase 3 clinical investigation in multiple myeloma (MM) in combination with lenalidomide–dexamethasone. This study was conducted to investigate the pharmacokinetic and safety profiles of ixazomib, administered with lenalidomide–dexamethasone, in East Asian patients with relapsed/refractory MM. METHODS: Adult patients with measurable disease who had received 1–3 prior lines of therapy received oral ixazomib on days 1, 8, and 15, lenalidomide (25 mg) on days 1–21, and dexamethasone (40 mg) on days 1, 8, 15, and 22, in 28-day cycles. Primary objectives were to characterize ixazomib plasma pharmacokinetics, determine the recommended phase 2/3 dose, and evaluate safety and tolerability. RESULTS: Forty-three patients were enrolled. No dose-limiting toxicities were reported for the first six patients receiving ixazomib (4.0 mg), confirming this as the recommended phase 2/3 dose. Ixazomib was rapidly absorbed with a median T(max) of 1.5 h on day 1 and 2.0 h on day 15 of cycle 1 and had a geometric mean terminal half-life of 6.1 days. Twenty-one (49 %) patients had at least one drug-related grade ≥3 adverse event (AE); the most common were neutropenia (19 %), diarrhea (14 %), and thrombocytopenia (12 %). Twenty-eight of 43 (65 %) response-evaluable patients had at least a partial response. The recommended phase 2/3 dose for ixazomib was determined to be 4.0 mg. CONCLUSIONS: The all-oral combination of ixazomib plus lenalidomide–dexamethasone appeared active and well tolerated at 4.0 mg. Consequently, East Asian patients enrolled in phase 3 studies are receiving the same ixazomib dose as patients in other regions. TRIAL REGISTRATION: This study is registered at NCT01645930. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13045-015-0198-1) contains supplementary material, which is available to authorized users. BioMed Central 2015-09-04 /pmc/articles/PMC4559079/ /pubmed/26337806 http://dx.doi.org/10.1186/s13045-015-0198-1 Text en © Gupta et al. 2015 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Gupta, Neeraj Goh, Yeow Tee Min, Chang-Ki Lee, Jae Hoon Kim, Kihyun Wong, Raymond S. M. Chim, Chor Sang Hanley, Michael J. Yang, Huyuan Venkatakrishnan, Karthik Hui, Ai-Min Esseltine, Dixie-Lee Chng, Wee Joo Pharmacokinetics and safety of ixazomib plus lenalidomide–dexamethasone in Asian patients with relapsed/refractory myeloma: a phase 1 study |
title | Pharmacokinetics and safety of ixazomib plus lenalidomide–dexamethasone in Asian patients with relapsed/refractory myeloma: a phase 1 study |
title_full | Pharmacokinetics and safety of ixazomib plus lenalidomide–dexamethasone in Asian patients with relapsed/refractory myeloma: a phase 1 study |
title_fullStr | Pharmacokinetics and safety of ixazomib plus lenalidomide–dexamethasone in Asian patients with relapsed/refractory myeloma: a phase 1 study |
title_full_unstemmed | Pharmacokinetics and safety of ixazomib plus lenalidomide–dexamethasone in Asian patients with relapsed/refractory myeloma: a phase 1 study |
title_short | Pharmacokinetics and safety of ixazomib plus lenalidomide–dexamethasone in Asian patients with relapsed/refractory myeloma: a phase 1 study |
title_sort | pharmacokinetics and safety of ixazomib plus lenalidomide–dexamethasone in asian patients with relapsed/refractory myeloma: a phase 1 study |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559079/ https://www.ncbi.nlm.nih.gov/pubmed/26337806 http://dx.doi.org/10.1186/s13045-015-0198-1 |
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