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Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours

BACKGROUND: In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours. METHODS: Adults with various solid tumours refractory...

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Autores principales: Hong, David S., Kang, Yoon-Koo, Borad, Mitesh, Sachdev, Jasgit, Ejadi, Samuel, Lim, Ho Yeong, Brenner, Andrew J., Park, Keunchil, Lee, Jae-Lyun, Kim, Tae-You, Shin, Sangjoon, Becerra, Carlos R., Falchook, Gerald, Stoudemire, Jay, Martin, Desiree, Kelnar, Kevin, Peltier, Heidi, Bonato, Vinicius, Bader, Andreas G., Smith, Susan, Kim, Sinil, O’Neill, Vincent, Beg, Muhammad S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251107/
https://www.ncbi.nlm.nih.gov/pubmed/32238921
http://dx.doi.org/10.1038/s41416-020-0802-1
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author Hong, David S.
Kang, Yoon-Koo
Borad, Mitesh
Sachdev, Jasgit
Ejadi, Samuel
Lim, Ho Yeong
Brenner, Andrew J.
Park, Keunchil
Lee, Jae-Lyun
Kim, Tae-You
Shin, Sangjoon
Becerra, Carlos R.
Falchook, Gerald
Stoudemire, Jay
Martin, Desiree
Kelnar, Kevin
Peltier, Heidi
Bonato, Vinicius
Bader, Andreas G.
Smith, Susan
Kim, Sinil
O’Neill, Vincent
Beg, Muhammad S.
author_facet Hong, David S.
Kang, Yoon-Koo
Borad, Mitesh
Sachdev, Jasgit
Ejadi, Samuel
Lim, Ho Yeong
Brenner, Andrew J.
Park, Keunchil
Lee, Jae-Lyun
Kim, Tae-You
Shin, Sangjoon
Becerra, Carlos R.
Falchook, Gerald
Stoudemire, Jay
Martin, Desiree
Kelnar, Kevin
Peltier, Heidi
Bonato, Vinicius
Bader, Andreas G.
Smith, Susan
Kim, Sinil
O’Neill, Vincent
Beg, Muhammad S.
author_sort Hong, David S.
collection PubMed
description BACKGROUND: In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours. METHODS: Adults with various solid tumours refractory to standard treatments were enrolled in 3 + 3 dose-escalation cohorts and, following RP2D determination, expansion cohorts. MRX34, with oral dexamethasone premedication, was given intravenously daily for 5 days in 3-week cycles. RESULTS: Common all-cause adverse events observed in 85 patients enrolled included fever (% all grade/G3: 72/4), chills (53/14), fatigue (51/9), back/neck pain (36/5), nausea (36/1) and dyspnoea (25/4). The RP2D was 70 mg/m(2) for hepatocellular carcinoma (HCC) and 93 mg/m(2) for non-HCC cancers. Pharmacodynamic results showed delivery of miR-34a to tumours, and dose-dependent modulation of target gene expression in white blood cells. Three patients had PRs and 16 had SD lasting ≥4 cycles (median, 19 weeks, range, 11–55). CONCLUSION: MRX34 treatment with dexamethasone premedication demonstrated a manageable toxicity profile in most patients and some clinical activity. Although the trial was closed early due to serious immune-mediated AEs that resulted in four patient deaths, dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy. CLINICAL TRIAL REGISTRATION: NCT01829971.
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spelling pubmed-72511072021-04-02 Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours Hong, David S. Kang, Yoon-Koo Borad, Mitesh Sachdev, Jasgit Ejadi, Samuel Lim, Ho Yeong Brenner, Andrew J. Park, Keunchil Lee, Jae-Lyun Kim, Tae-You Shin, Sangjoon Becerra, Carlos R. Falchook, Gerald Stoudemire, Jay Martin, Desiree Kelnar, Kevin Peltier, Heidi Bonato, Vinicius Bader, Andreas G. Smith, Susan Kim, Sinil O’Neill, Vincent Beg, Muhammad S. Br J Cancer Article BACKGROUND: In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours. METHODS: Adults with various solid tumours refractory to standard treatments were enrolled in 3 + 3 dose-escalation cohorts and, following RP2D determination, expansion cohorts. MRX34, with oral dexamethasone premedication, was given intravenously daily for 5 days in 3-week cycles. RESULTS: Common all-cause adverse events observed in 85 patients enrolled included fever (% all grade/G3: 72/4), chills (53/14), fatigue (51/9), back/neck pain (36/5), nausea (36/1) and dyspnoea (25/4). The RP2D was 70 mg/m(2) for hepatocellular carcinoma (HCC) and 93 mg/m(2) for non-HCC cancers. Pharmacodynamic results showed delivery of miR-34a to tumours, and dose-dependent modulation of target gene expression in white blood cells. Three patients had PRs and 16 had SD lasting ≥4 cycles (median, 19 weeks, range, 11–55). CONCLUSION: MRX34 treatment with dexamethasone premedication demonstrated a manageable toxicity profile in most patients and some clinical activity. Although the trial was closed early due to serious immune-mediated AEs that resulted in four patient deaths, dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy. CLINICAL TRIAL REGISTRATION: NCT01829971. Nature Publishing Group UK 2020-04-02 2020-05-26 /pmc/articles/PMC7251107/ /pubmed/32238921 http://dx.doi.org/10.1038/s41416-020-0802-1 Text en © The Author(s), under exclusive licence to Cancer Research UK 2020 https://creativecommons.org/licenses/by/4.0/Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).
spellingShingle Article
Hong, David S.
Kang, Yoon-Koo
Borad, Mitesh
Sachdev, Jasgit
Ejadi, Samuel
Lim, Ho Yeong
Brenner, Andrew J.
Park, Keunchil
Lee, Jae-Lyun
Kim, Tae-You
Shin, Sangjoon
Becerra, Carlos R.
Falchook, Gerald
Stoudemire, Jay
Martin, Desiree
Kelnar, Kevin
Peltier, Heidi
Bonato, Vinicius
Bader, Andreas G.
Smith, Susan
Kim, Sinil
O’Neill, Vincent
Beg, Muhammad S.
Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours
title Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours
title_full Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours
title_fullStr Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours
title_full_unstemmed Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours
title_short Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours
title_sort phase 1 study of mrx34, a liposomal mir-34a mimic, in patients with advanced solid tumours
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251107/
https://www.ncbi.nlm.nih.gov/pubmed/32238921
http://dx.doi.org/10.1038/s41416-020-0802-1
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