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A phase I study of high-dose rosuvastatin with standard dose erlotinib in patients with advanced solid malignancies

BACKGROUND: Synergistic cytotoxicity with high-dose statins and erlotinib has been demonstrated in preclinical models across a number of tumour types. In this phase I study, we evaluated the safety and potential anti-tumour activity of escalating doses of rosuvastatin in combination with the standar...

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Autores principales: Goss, Glenwood D., Jonker, Derek J., Laurie, Scott A., Weberpals, Johanne I., Oza, Amit M., Spaans, Johanna N., la Porte, Charles, Dimitroulakos, Jim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815068/
https://www.ncbi.nlm.nih.gov/pubmed/27036206
http://dx.doi.org/10.1186/s12967-016-0836-6
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author Goss, Glenwood D.
Jonker, Derek J.
Laurie, Scott A.
Weberpals, Johanne I.
Oza, Amit M.
Spaans, Johanna N.
la Porte, Charles
Dimitroulakos, Jim
author_facet Goss, Glenwood D.
Jonker, Derek J.
Laurie, Scott A.
Weberpals, Johanne I.
Oza, Amit M.
Spaans, Johanna N.
la Porte, Charles
Dimitroulakos, Jim
author_sort Goss, Glenwood D.
collection PubMed
description BACKGROUND: Synergistic cytotoxicity with high-dose statins and erlotinib has been demonstrated in preclinical models across a number of tumour types. In this phase I study, we evaluated the safety and potential anti-tumour activity of escalating doses of rosuvastatin in combination with the standard clinical dose of erlotinib in heavily pretreated patients with advanced solid tumours. METHODS: This was a single-center, phase I open-label study to determine the safety and recommended phase two dose (RPTD) of rosuvastatin in combination with 150 mg/day standard dose of erlotinib. Using a 3 + 3 study design and 28-day cycle, escalating doses of rosuvastatin from 1 to 8 mg/kg/day ×2 weeks (cycle 1) and 3 weeks (subsequent cycles) given concurrently with erlotinib were evaluated. In order to expand the experience and to gain additional safety and pharmacokinetic data, two expansions cohorts using concurrent or alternating weekly dosing regimens at the RPTD were also evaluated. RESULTS: All 24 patients enrolled were evaluable for toxicity, and 22 for response. The dose-limiting toxicity (DLT) of reversible muscle toxicity was seen at the 2 mg/kg/day dose level. Maximal tolerated dose (MTD) was determined to be 1 mg/kg/day. Thirty-three percent of patients developed at least 1≥ grade 2 muscle toxicity (rhabdomyolysis: 1/24, myalgia: 7/24) resulting in one study-related death. Durable stable disease for more than 170 days was seen in 25 % of patients that received concurrent treatment and were evaluable for response (n = 16). Plasma erlotinib levels on study were unaffected by the addition of rosuvastatin. CONCLUSIONS: The observed disease stabilization rate of 25 % with combination therapy in this heavily pretreated population is encouraging, however, the high levels of muscle toxicities observed limited this combination strategy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12967-016-0836-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-48150682016-04-01 A phase I study of high-dose rosuvastatin with standard dose erlotinib in patients with advanced solid malignancies Goss, Glenwood D. Jonker, Derek J. Laurie, Scott A. Weberpals, Johanne I. Oza, Amit M. Spaans, Johanna N. la Porte, Charles Dimitroulakos, Jim J Transl Med Research BACKGROUND: Synergistic cytotoxicity with high-dose statins and erlotinib has been demonstrated in preclinical models across a number of tumour types. In this phase I study, we evaluated the safety and potential anti-tumour activity of escalating doses of rosuvastatin in combination with the standard clinical dose of erlotinib in heavily pretreated patients with advanced solid tumours. METHODS: This was a single-center, phase I open-label study to determine the safety and recommended phase two dose (RPTD) of rosuvastatin in combination with 150 mg/day standard dose of erlotinib. Using a 3 + 3 study design and 28-day cycle, escalating doses of rosuvastatin from 1 to 8 mg/kg/day ×2 weeks (cycle 1) and 3 weeks (subsequent cycles) given concurrently with erlotinib were evaluated. In order to expand the experience and to gain additional safety and pharmacokinetic data, two expansions cohorts using concurrent or alternating weekly dosing regimens at the RPTD were also evaluated. RESULTS: All 24 patients enrolled were evaluable for toxicity, and 22 for response. The dose-limiting toxicity (DLT) of reversible muscle toxicity was seen at the 2 mg/kg/day dose level. Maximal tolerated dose (MTD) was determined to be 1 mg/kg/day. Thirty-three percent of patients developed at least 1≥ grade 2 muscle toxicity (rhabdomyolysis: 1/24, myalgia: 7/24) resulting in one study-related death. Durable stable disease for more than 170 days was seen in 25 % of patients that received concurrent treatment and were evaluable for response (n = 16). Plasma erlotinib levels on study were unaffected by the addition of rosuvastatin. CONCLUSIONS: The observed disease stabilization rate of 25 % with combination therapy in this heavily pretreated population is encouraging, however, the high levels of muscle toxicities observed limited this combination strategy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12967-016-0836-6) contains supplementary material, which is available to authorized users. BioMed Central 2016-03-31 /pmc/articles/PMC4815068/ /pubmed/27036206 http://dx.doi.org/10.1186/s12967-016-0836-6 Text en © Goss et al. 2016 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
Goss, Glenwood D.
Jonker, Derek J.
Laurie, Scott A.
Weberpals, Johanne I.
Oza, Amit M.
Spaans, Johanna N.
la Porte, Charles
Dimitroulakos, Jim
A phase I study of high-dose rosuvastatin with standard dose erlotinib in patients with advanced solid malignancies
title A phase I study of high-dose rosuvastatin with standard dose erlotinib in patients with advanced solid malignancies
title_full A phase I study of high-dose rosuvastatin with standard dose erlotinib in patients with advanced solid malignancies
title_fullStr A phase I study of high-dose rosuvastatin with standard dose erlotinib in patients with advanced solid malignancies
title_full_unstemmed A phase I study of high-dose rosuvastatin with standard dose erlotinib in patients with advanced solid malignancies
title_short A phase I study of high-dose rosuvastatin with standard dose erlotinib in patients with advanced solid malignancies
title_sort phase i study of high-dose rosuvastatin with standard dose erlotinib in patients with advanced solid malignancies
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815068/
https://www.ncbi.nlm.nih.gov/pubmed/27036206
http://dx.doi.org/10.1186/s12967-016-0836-6
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