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A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer

BACKGROUND: Targeted therapies in HER2-positive metastatic breast cancer significantly improve outcomes but efficacy is limited by therapeutic resistance. HER2 is an acutely sensitive Heat Shock Protein 90 (HSP90) client and HSP90 inhibition can overcome trastuzumab resistance. Preclinical data sugg...

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Autores principales: Jhaveri, Komal, Wang, Rui, Teplinsky, Eleonora, Chandarlapaty, Sarat, Solit, David, Cadoo, Karen, Speyer, James, D’Andrea, Gabriella, Adams, Sylvia, Patil, Sujata, Haque, Sofia, O’Neill, Tara, Friedman, Kent, Esteva, Francisco J., Hudis, Clifford, Modi, Shanu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540198/
https://www.ncbi.nlm.nih.gov/pubmed/28764748
http://dx.doi.org/10.1186/s13058-017-0879-5
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author Jhaveri, Komal
Wang, Rui
Teplinsky, Eleonora
Chandarlapaty, Sarat
Solit, David
Cadoo, Karen
Speyer, James
D’Andrea, Gabriella
Adams, Sylvia
Patil, Sujata
Haque, Sofia
O’Neill, Tara
Friedman, Kent
Esteva, Francisco J.
Hudis, Clifford
Modi, Shanu
author_facet Jhaveri, Komal
Wang, Rui
Teplinsky, Eleonora
Chandarlapaty, Sarat
Solit, David
Cadoo, Karen
Speyer, James
D’Andrea, Gabriella
Adams, Sylvia
Patil, Sujata
Haque, Sofia
O’Neill, Tara
Friedman, Kent
Esteva, Francisco J.
Hudis, Clifford
Modi, Shanu
author_sort Jhaveri, Komal
collection PubMed
description BACKGROUND: Targeted therapies in HER2-positive metastatic breast cancer significantly improve outcomes but efficacy is limited by therapeutic resistance. HER2 is an acutely sensitive Heat Shock Protein 90 (HSP90) client and HSP90 inhibition can overcome trastuzumab resistance. Preclinical data suggest that HSP90 inhibition is synergistic with taxanes with the potential for significant clinical activity. We therefore tested ganetespib, a HSP90 inhibitor, in combination with paclitaxel and trastuzumab in patients with trastuzumab-refractory HER2-positive metastatic breast cancer. METHODS: In this phase I dose-escalation study, patients with trastuzumab-resistant HER2-positive metastatic breast cancer received weekly trastuzumab (2 mg/kg) and paclitaxel (80 mg/m(2)) on days 1, 8, 15, and 22 of a 28-day cycle with escalating doses of ganetespib (100 mg/m(2), 150 mg/m(2), and a third cohort of 125 mg/m(2) if needed) on days 1, 8, and 15. Therapy was continued until disease progression or toxicity. The primary objective was to establish the safety and maximum tolerated dose and/or recommended phase II dose (RP2D) of this therapy. The secondary objectives included evaluation of the effects of ganetespib on the pharmacokinetics of paclitaxel, and to make a preliminary assessment of the efficacy of the combination therapy. RESULTS: Dose escalation was completed for the two main cohorts without any observed dose-limiting toxicities. Nine patients received treatment. The median prior lines of anti-HER2 therapy numbered three (range 2–4), including prior pertuzumab in 9/9 patients and ado-trastuzumab emtansine (T-DM1) in 8/9 patients. The most common grade 1/2 adverse events (AEs) were diarrhea, fatigue, anemia, and rash. There were no grade 4 AEs related to ganetespib. The overall response rate was 22% (2/9 patients had partial response) and stable disease was seen in 56% (5/9 patients). The clinical benefit rate was 44% (4/9 patients). The median progression-free survival was 20 weeks (range 8–55). CONCLUSION: The RP2D of ganetespib is 150 mg/m(2) in combination with weekly paclitaxel plus trastuzumab. The combination was safe and well tolerated. Despite prior taxanes, pertuzumab, and T-DM1, clinical activity of this triplet regimen in this heavily pretreated cohort is promising and warrants further study in HER2-positive metastatic breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT02060253. Registered 30 January 2014.
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spelling pubmed-55401982017-08-03 A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer Jhaveri, Komal Wang, Rui Teplinsky, Eleonora Chandarlapaty, Sarat Solit, David Cadoo, Karen Speyer, James D’Andrea, Gabriella Adams, Sylvia Patil, Sujata Haque, Sofia O’Neill, Tara Friedman, Kent Esteva, Francisco J. Hudis, Clifford Modi, Shanu Breast Cancer Res Research Article BACKGROUND: Targeted therapies in HER2-positive metastatic breast cancer significantly improve outcomes but efficacy is limited by therapeutic resistance. HER2 is an acutely sensitive Heat Shock Protein 90 (HSP90) client and HSP90 inhibition can overcome trastuzumab resistance. Preclinical data suggest that HSP90 inhibition is synergistic with taxanes with the potential for significant clinical activity. We therefore tested ganetespib, a HSP90 inhibitor, in combination with paclitaxel and trastuzumab in patients with trastuzumab-refractory HER2-positive metastatic breast cancer. METHODS: In this phase I dose-escalation study, patients with trastuzumab-resistant HER2-positive metastatic breast cancer received weekly trastuzumab (2 mg/kg) and paclitaxel (80 mg/m(2)) on days 1, 8, 15, and 22 of a 28-day cycle with escalating doses of ganetespib (100 mg/m(2), 150 mg/m(2), and a third cohort of 125 mg/m(2) if needed) on days 1, 8, and 15. Therapy was continued until disease progression or toxicity. The primary objective was to establish the safety and maximum tolerated dose and/or recommended phase II dose (RP2D) of this therapy. The secondary objectives included evaluation of the effects of ganetespib on the pharmacokinetics of paclitaxel, and to make a preliminary assessment of the efficacy of the combination therapy. RESULTS: Dose escalation was completed for the two main cohorts without any observed dose-limiting toxicities. Nine patients received treatment. The median prior lines of anti-HER2 therapy numbered three (range 2–4), including prior pertuzumab in 9/9 patients and ado-trastuzumab emtansine (T-DM1) in 8/9 patients. The most common grade 1/2 adverse events (AEs) were diarrhea, fatigue, anemia, and rash. There were no grade 4 AEs related to ganetespib. The overall response rate was 22% (2/9 patients had partial response) and stable disease was seen in 56% (5/9 patients). The clinical benefit rate was 44% (4/9 patients). The median progression-free survival was 20 weeks (range 8–55). CONCLUSION: The RP2D of ganetespib is 150 mg/m(2) in combination with weekly paclitaxel plus trastuzumab. The combination was safe and well tolerated. Despite prior taxanes, pertuzumab, and T-DM1, clinical activity of this triplet regimen in this heavily pretreated cohort is promising and warrants further study in HER2-positive metastatic breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT02060253. Registered 30 January 2014. BioMed Central 2017-08-02 2017 /pmc/articles/PMC5540198/ /pubmed/28764748 http://dx.doi.org/10.1186/s13058-017-0879-5 Text en © The Author(s). 2017 Open AccessThis 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
Jhaveri, Komal
Wang, Rui
Teplinsky, Eleonora
Chandarlapaty, Sarat
Solit, David
Cadoo, Karen
Speyer, James
D’Andrea, Gabriella
Adams, Sylvia
Patil, Sujata
Haque, Sofia
O’Neill, Tara
Friedman, Kent
Esteva, Francisco J.
Hudis, Clifford
Modi, Shanu
A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer
title A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer
title_full A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer
title_fullStr A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer
title_full_unstemmed A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer
title_short A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer
title_sort phase i trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (her2)-positive metastatic breast cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540198/
https://www.ncbi.nlm.nih.gov/pubmed/28764748
http://dx.doi.org/10.1186/s13058-017-0879-5
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