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Ixazomib in combination with carboplatin in pretreated women with advanced triple-negative breast cancer, a phase I/II trial of the AGMT (AGMT MBC-10 trial)
BACKGROUND: Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. Up to now, no targeted treatment beyond anti-VEGF therapy has been approved for TNBC and cytotoxic agents remain the mainstay of treatment. Ixazomib is a s...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220453/ https://www.ncbi.nlm.nih.gov/pubmed/30400780 http://dx.doi.org/10.1186/s12885-018-4979-0 |
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author | Rinnerthaler, Gabriel Gampenrieder, Simon Peter Petzer, Andreas Burgstaller, Sonja Fuchs, David Rossmann, Dieter Balic, Marija Egle, Daniel Rumpold, Holger Singer, Christian F. Bartsch, Rupert Petru, Edgar Melchardt, Thomas Ulmer, Hanno Mlineritsch, Brigitte Greil, Richard |
author_facet | Rinnerthaler, Gabriel Gampenrieder, Simon Peter Petzer, Andreas Burgstaller, Sonja Fuchs, David Rossmann, Dieter Balic, Marija Egle, Daniel Rumpold, Holger Singer, Christian F. Bartsch, Rupert Petru, Edgar Melchardt, Thomas Ulmer, Hanno Mlineritsch, Brigitte Greil, Richard |
author_sort | Rinnerthaler, Gabriel |
collection | PubMed |
description | BACKGROUND: Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. Up to now, no targeted treatment beyond anti-VEGF therapy has been approved for TNBC and cytotoxic agents remain the mainstay of treatment. Ixazomib is a selective and reversible inhibitor of the proteasome, which has been mainly investigated in the treatment of multiple myeloma. In a preclinical study TNBC cells were treated with the first-generation proteasome inhibitor bortezomib in combination with cisplatin and synergistic efficacy was demonstrated. Clinical data are available for carboplatin plus bortezomib in metastatic ovarian and lung cancers showing remarkable antitumor activity and good tolerability (Mol Cancer 11:26 2012, J Thorac Oncol 4:87–92 2009, J Thorac Oncol 7:1032–1040, 2012). Based on this evidence, the phase I/II MBC-10 trial will evaluate the toxicity profile and efficacy of the second-generation proteasome inhibitor ixazomib in combination with carboplatin in patients with advanced TNBC. METHODS: Patients with metastatic TNBC pretreated with at least one prior line of chemotherapy for advanced disease with a confirmed disease progression and measurable disease according to RECIST criteria 1.1 are eligible for this study. Patients will receive ixazomib in combination with carboplatin on days 1, 8, and 15 in a 28-day cycle. The phase I part of this study utilizes an alternate dose escalation accelerated titration design. After establishing the maximum tolerated dose (MTD), the efficacy and safety of the combination will be further evaluated (phase II, including 41 evaluable patients). All patients will continue on study drugs until disease progression, unacceptable toxicity or discontinuation for any other reason. Primary endpoint of the phase II is overall response rate, secondary endpoints include progression-free survival, safety, and quality of life. This trial is open for patient enrollment since November 2016 in six Austrian cancer centers. Accrual is planned to be completed within 2 years. DISCUSSION: Based on preclinical and clinical findings an ixazomib and carboplatin combination is thought to be effective in metastatic TNBC patients. The MBC-10 trial is accompanied by a broad biomarker program investigating predictive biomarkers for treatment response and potential resistance mechanisms to the investigational drug combination. TRIAL REGISTRATION: EudraCT Number: 2016–001421-13 received on March 31, 2016, ClinicalTrials.gov Identifier: NCT02993094 first posted on December 15, 2016. This trial was registered prospectively. |
format | Online Article Text |
id | pubmed-6220453 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-62204532018-11-16 Ixazomib in combination with carboplatin in pretreated women with advanced triple-negative breast cancer, a phase I/II trial of the AGMT (AGMT MBC-10 trial) Rinnerthaler, Gabriel Gampenrieder, Simon Peter Petzer, Andreas Burgstaller, Sonja Fuchs, David Rossmann, Dieter Balic, Marija Egle, Daniel Rumpold, Holger Singer, Christian F. Bartsch, Rupert Petru, Edgar Melchardt, Thomas Ulmer, Hanno Mlineritsch, Brigitte Greil, Richard BMC Cancer Study Protocol BACKGROUND: Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. Up to now, no targeted treatment beyond anti-VEGF therapy has been approved for TNBC and cytotoxic agents remain the mainstay of treatment. Ixazomib is a selective and reversible inhibitor of the proteasome, which has been mainly investigated in the treatment of multiple myeloma. In a preclinical study TNBC cells were treated with the first-generation proteasome inhibitor bortezomib in combination with cisplatin and synergistic efficacy was demonstrated. Clinical data are available for carboplatin plus bortezomib in metastatic ovarian and lung cancers showing remarkable antitumor activity and good tolerability (Mol Cancer 11:26 2012, J Thorac Oncol 4:87–92 2009, J Thorac Oncol 7:1032–1040, 2012). Based on this evidence, the phase I/II MBC-10 trial will evaluate the toxicity profile and efficacy of the second-generation proteasome inhibitor ixazomib in combination with carboplatin in patients with advanced TNBC. METHODS: Patients with metastatic TNBC pretreated with at least one prior line of chemotherapy for advanced disease with a confirmed disease progression and measurable disease according to RECIST criteria 1.1 are eligible for this study. Patients will receive ixazomib in combination with carboplatin on days 1, 8, and 15 in a 28-day cycle. The phase I part of this study utilizes an alternate dose escalation accelerated titration design. After establishing the maximum tolerated dose (MTD), the efficacy and safety of the combination will be further evaluated (phase II, including 41 evaluable patients). All patients will continue on study drugs until disease progression, unacceptable toxicity or discontinuation for any other reason. Primary endpoint of the phase II is overall response rate, secondary endpoints include progression-free survival, safety, and quality of life. This trial is open for patient enrollment since November 2016 in six Austrian cancer centers. Accrual is planned to be completed within 2 years. DISCUSSION: Based on preclinical and clinical findings an ixazomib and carboplatin combination is thought to be effective in metastatic TNBC patients. The MBC-10 trial is accompanied by a broad biomarker program investigating predictive biomarkers for treatment response and potential resistance mechanisms to the investigational drug combination. TRIAL REGISTRATION: EudraCT Number: 2016–001421-13 received on March 31, 2016, ClinicalTrials.gov Identifier: NCT02993094 first posted on December 15, 2016. This trial was registered prospectively. BioMed Central 2018-11-06 /pmc/articles/PMC6220453/ /pubmed/30400780 http://dx.doi.org/10.1186/s12885-018-4979-0 Text en © The Author(s). 2018 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 | Study Protocol Rinnerthaler, Gabriel Gampenrieder, Simon Peter Petzer, Andreas Burgstaller, Sonja Fuchs, David Rossmann, Dieter Balic, Marija Egle, Daniel Rumpold, Holger Singer, Christian F. Bartsch, Rupert Petru, Edgar Melchardt, Thomas Ulmer, Hanno Mlineritsch, Brigitte Greil, Richard Ixazomib in combination with carboplatin in pretreated women with advanced triple-negative breast cancer, a phase I/II trial of the AGMT (AGMT MBC-10 trial) |
title | Ixazomib in combination with carboplatin in pretreated women with advanced triple-negative breast cancer, a phase I/II trial of the AGMT (AGMT MBC-10 trial) |
title_full | Ixazomib in combination with carboplatin in pretreated women with advanced triple-negative breast cancer, a phase I/II trial of the AGMT (AGMT MBC-10 trial) |
title_fullStr | Ixazomib in combination with carboplatin in pretreated women with advanced triple-negative breast cancer, a phase I/II trial of the AGMT (AGMT MBC-10 trial) |
title_full_unstemmed | Ixazomib in combination with carboplatin in pretreated women with advanced triple-negative breast cancer, a phase I/II trial of the AGMT (AGMT MBC-10 trial) |
title_short | Ixazomib in combination with carboplatin in pretreated women with advanced triple-negative breast cancer, a phase I/II trial of the AGMT (AGMT MBC-10 trial) |
title_sort | ixazomib in combination with carboplatin in pretreated women with advanced triple-negative breast cancer, a phase i/ii trial of the agmt (agmt mbc-10 trial) |
topic | Study Protocol |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220453/ https://www.ncbi.nlm.nih.gov/pubmed/30400780 http://dx.doi.org/10.1186/s12885-018-4979-0 |
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