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A Phase Ib/II Study of Ganetespib With Doxorubicin in Advanced Solid Tumors Including Relapsed-Refractory Small Cell Lung Cancer

INTRODUCTION: Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and is characterized by high response rates to cytotoxic chemotherapy and equally high rates of relapse. Many resistance mechanisms have been proposed including resistance to doxorubicin via induction of a heat shock re...

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Autores principales: Subramaniam, Deepa S., Liu, Stephen V., Crawford, Jeanette, Kramer, Jenna, Thompson, Jillian, Wang, Hongkun, Giaccone, Giuseppe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858550/
https://www.ncbi.nlm.nih.gov/pubmed/29594044
http://dx.doi.org/10.3389/fonc.2018.00064
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author Subramaniam, Deepa S.
Liu, Stephen V.
Crawford, Jeanette
Kramer, Jenna
Thompson, Jillian
Wang, Hongkun
Giaccone, Giuseppe
author_facet Subramaniam, Deepa S.
Liu, Stephen V.
Crawford, Jeanette
Kramer, Jenna
Thompson, Jillian
Wang, Hongkun
Giaccone, Giuseppe
author_sort Subramaniam, Deepa S.
collection PubMed
description INTRODUCTION: Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and is characterized by high response rates to cytotoxic chemotherapy and equally high rates of relapse. Many resistance mechanisms have been proposed including resistance to doxorubicin via induction of a heat shock response. Ganetespib is a novel and potent non-geldanamycin heat shock protein 90 (Hsp90) inhibitor. In preclinical studies, synergy between ganetespib and doxorubicin was shown. We conducted a phase Ib/II study of the safety, tolerability, and preliminary efficacy of the combination of ganetespib and doxorubicin. METHODS: Patients eligible for the phase Ib portion had advanced tumors that would be appropriate for doxorubicin therapy and those in the phase II portion had relapsed or refractory SCLC. All patients had an ECOG performance status, 0–1 and adequate organ function, including a cardiac ejection fraction ≥50%. Patients who received a lifetime cumulative doxorubicin dose of >150 mg/m(2) or who had symptomatic brain metastases were excluded. Patients received ganetespib on Days 1 and 8 and doxorubicin 50 mg/m(2) on day 1 in 21-day cycles. RESULTS: Eleven patients were enrolled including nine in the phase Ib dose escalation and two in the phase II expansion. The study was terminated by the sponsor. The dose recommended for future study is ganetespib 150 mg/m(2) in combination with doxorubicin at a dose of 50 mg/m(2). The most common adverse events of the combination were grade 1/2 diarrhea, nausea, fatigue, and transaminitis. No dose limiting toxicities were observed. Response rate was 25% and median duration of response was 137 days. CONCLUSION: Ganetespib plus doxorubicin was a well-tolerated combination and there remains potential for the clinical development of Hsp90 inhibitors in SCLC. CLINICAL TRIAL REGISTRATION: https://ClinicalTrials.gov/ct2/show/NCT02261805, identifier NCT02261805.
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spelling pubmed-58585502018-03-28 A Phase Ib/II Study of Ganetespib With Doxorubicin in Advanced Solid Tumors Including Relapsed-Refractory Small Cell Lung Cancer Subramaniam, Deepa S. Liu, Stephen V. Crawford, Jeanette Kramer, Jenna Thompson, Jillian Wang, Hongkun Giaccone, Giuseppe Front Oncol Oncology INTRODUCTION: Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and is characterized by high response rates to cytotoxic chemotherapy and equally high rates of relapse. Many resistance mechanisms have been proposed including resistance to doxorubicin via induction of a heat shock response. Ganetespib is a novel and potent non-geldanamycin heat shock protein 90 (Hsp90) inhibitor. In preclinical studies, synergy between ganetespib and doxorubicin was shown. We conducted a phase Ib/II study of the safety, tolerability, and preliminary efficacy of the combination of ganetespib and doxorubicin. METHODS: Patients eligible for the phase Ib portion had advanced tumors that would be appropriate for doxorubicin therapy and those in the phase II portion had relapsed or refractory SCLC. All patients had an ECOG performance status, 0–1 and adequate organ function, including a cardiac ejection fraction ≥50%. Patients who received a lifetime cumulative doxorubicin dose of >150 mg/m(2) or who had symptomatic brain metastases were excluded. Patients received ganetespib on Days 1 and 8 and doxorubicin 50 mg/m(2) on day 1 in 21-day cycles. RESULTS: Eleven patients were enrolled including nine in the phase Ib dose escalation and two in the phase II expansion. The study was terminated by the sponsor. The dose recommended for future study is ganetespib 150 mg/m(2) in combination with doxorubicin at a dose of 50 mg/m(2). The most common adverse events of the combination were grade 1/2 diarrhea, nausea, fatigue, and transaminitis. No dose limiting toxicities were observed. Response rate was 25% and median duration of response was 137 days. CONCLUSION: Ganetespib plus doxorubicin was a well-tolerated combination and there remains potential for the clinical development of Hsp90 inhibitors in SCLC. CLINICAL TRIAL REGISTRATION: https://ClinicalTrials.gov/ct2/show/NCT02261805, identifier NCT02261805. Frontiers Media S.A. 2018-03-12 /pmc/articles/PMC5858550/ /pubmed/29594044 http://dx.doi.org/10.3389/fonc.2018.00064 Text en Copyright © 2018 Subramaniam, Liu, Crawford, Kramer, Thompson, Wang and Giaccone. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Subramaniam, Deepa S.
Liu, Stephen V.
Crawford, Jeanette
Kramer, Jenna
Thompson, Jillian
Wang, Hongkun
Giaccone, Giuseppe
A Phase Ib/II Study of Ganetespib With Doxorubicin in Advanced Solid Tumors Including Relapsed-Refractory Small Cell Lung Cancer
title A Phase Ib/II Study of Ganetespib With Doxorubicin in Advanced Solid Tumors Including Relapsed-Refractory Small Cell Lung Cancer
title_full A Phase Ib/II Study of Ganetespib With Doxorubicin in Advanced Solid Tumors Including Relapsed-Refractory Small Cell Lung Cancer
title_fullStr A Phase Ib/II Study of Ganetespib With Doxorubicin in Advanced Solid Tumors Including Relapsed-Refractory Small Cell Lung Cancer
title_full_unstemmed A Phase Ib/II Study of Ganetespib With Doxorubicin in Advanced Solid Tumors Including Relapsed-Refractory Small Cell Lung Cancer
title_short A Phase Ib/II Study of Ganetespib With Doxorubicin in Advanced Solid Tumors Including Relapsed-Refractory Small Cell Lung Cancer
title_sort phase ib/ii study of ganetespib with doxorubicin in advanced solid tumors including relapsed-refractory small cell lung cancer
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858550/
https://www.ncbi.nlm.nih.gov/pubmed/29594044
http://dx.doi.org/10.3389/fonc.2018.00064
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