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A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI♯9041)

Background There is crosstalk between the ANG-Tie2 and the PI3K/Akt/mTOR pathways. Combined ANG1/2 and mTOR blockade may have additive anti-cancer activity. The combination of trebananib, an inhibitor of ANG1/2-Tie2 interaction, with temsirolimus was evaluated in patients with advanced solid tumors...

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Autores principales: Chiu, Joanne W., Hotte, Sebastien J., Kollmannsberger, Christian K., Renouf, Daniel J., Cescon, David W., Hedley, David, Chow, Sue, Moscow, Jeffrey, Chen, Zhuo, Perry, Meghan, Diaz-Padilla, Ivan, Tan, David, Hirte, Hal, McWhirter, Elaine, Chen, Helen, Siu, Lillian L., Bedard, Philippe L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718956/
https://www.ncbi.nlm.nih.gov/pubmed/26686201
http://dx.doi.org/10.1007/s10637-015-0313-8
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author Chiu, Joanne W.
Hotte, Sebastien J.
Kollmannsberger, Christian K.
Renouf, Daniel J.
Cescon, David W.
Hedley, David
Chow, Sue
Moscow, Jeffrey
Chen, Zhuo
Perry, Meghan
Diaz-Padilla, Ivan
Tan, David
Hirte, Hal
McWhirter, Elaine
Chen, Helen
Siu, Lillian L.
Bedard, Philippe L.
author_facet Chiu, Joanne W.
Hotte, Sebastien J.
Kollmannsberger, Christian K.
Renouf, Daniel J.
Cescon, David W.
Hedley, David
Chow, Sue
Moscow, Jeffrey
Chen, Zhuo
Perry, Meghan
Diaz-Padilla, Ivan
Tan, David
Hirte, Hal
McWhirter, Elaine
Chen, Helen
Siu, Lillian L.
Bedard, Philippe L.
author_sort Chiu, Joanne W.
collection PubMed
description Background There is crosstalk between the ANG-Tie2 and the PI3K/Akt/mTOR pathways. Combined ANG1/2 and mTOR blockade may have additive anti-cancer activity. The combination of trebananib, an inhibitor of ANG1/2-Tie2 interaction, with temsirolimus was evaluated in patients with advanced solid tumors to determine tolerability, maximum tolerated dose (MTD), and preliminary antitumor activity. Methods Patients were enrolled using 3 + 3 design, and were given intravenous trebananib and temsirolimus on Day 1, 8, 15 and 22 of a 28-day cycle. Dose limiting toxicities (DLTs) were evaluated during cycle 1. Peripheral blood was collected for evaluation of Tie2-expressing monocytes (TEMs) and thymidine phosphorylase (TP). Sparse pharmacokinetic (PK) sampling for trebananib drug levels was performed on Day 1 and 8 of cycle 2. Results Twenty-one patients were enrolled, 6 at dose level (DL) 1, 7 at DL −1, and 8 at DL −2. No effect of temsirolimus on trebananib PK was observed. The most common treatment-related adverse events (AEs) were: fatigue (81 %), edema (62 %), anorexia (57 %), nausea (52 %), rash (43 %) and mucositis (43 %). The most common grade ≥ 3 AEs included lymphopenia (28 %) and fatigue (28 %). The MTD was exceeded at DL-2. Of 18 response evaluable patients, 1 partial response was observed (ER+/HER2−/PIK3CA mutant breast cancer) and 4 patients had prolonged SD ≥ 24 weeks. No correlation with clinical benefit was observed with change in number TEMs or TP expression in TEMs with treatment. Conclusions The MTD was exceeded at trebananib 10 mg/kg weekly and temsirolimus 20 mg weekly, with frequent overlapping toxicities including fatigue, edema, and anorexia. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10637-015-0313-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-47189562016-01-27 A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI♯9041) Chiu, Joanne W. Hotte, Sebastien J. Kollmannsberger, Christian K. Renouf, Daniel J. Cescon, David W. Hedley, David Chow, Sue Moscow, Jeffrey Chen, Zhuo Perry, Meghan Diaz-Padilla, Ivan Tan, David Hirte, Hal McWhirter, Elaine Chen, Helen Siu, Lillian L. Bedard, Philippe L. Invest New Drugs Phase I Studies Background There is crosstalk between the ANG-Tie2 and the PI3K/Akt/mTOR pathways. Combined ANG1/2 and mTOR blockade may have additive anti-cancer activity. The combination of trebananib, an inhibitor of ANG1/2-Tie2 interaction, with temsirolimus was evaluated in patients with advanced solid tumors to determine tolerability, maximum tolerated dose (MTD), and preliminary antitumor activity. Methods Patients were enrolled using 3 + 3 design, and were given intravenous trebananib and temsirolimus on Day 1, 8, 15 and 22 of a 28-day cycle. Dose limiting toxicities (DLTs) were evaluated during cycle 1. Peripheral blood was collected for evaluation of Tie2-expressing monocytes (TEMs) and thymidine phosphorylase (TP). Sparse pharmacokinetic (PK) sampling for trebananib drug levels was performed on Day 1 and 8 of cycle 2. Results Twenty-one patients were enrolled, 6 at dose level (DL) 1, 7 at DL −1, and 8 at DL −2. No effect of temsirolimus on trebananib PK was observed. The most common treatment-related adverse events (AEs) were: fatigue (81 %), edema (62 %), anorexia (57 %), nausea (52 %), rash (43 %) and mucositis (43 %). The most common grade ≥ 3 AEs included lymphopenia (28 %) and fatigue (28 %). The MTD was exceeded at DL-2. Of 18 response evaluable patients, 1 partial response was observed (ER+/HER2−/PIK3CA mutant breast cancer) and 4 patients had prolonged SD ≥ 24 weeks. No correlation with clinical benefit was observed with change in number TEMs or TP expression in TEMs with treatment. Conclusions The MTD was exceeded at trebananib 10 mg/kg weekly and temsirolimus 20 mg weekly, with frequent overlapping toxicities including fatigue, edema, and anorexia. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10637-015-0313-8) contains supplementary material, which is available to authorized users. Springer US 2015-12-19 2016 /pmc/articles/PMC4718956/ /pubmed/26686201 http://dx.doi.org/10.1007/s10637-015-0313-8 Text en © The Author(s) 2015 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.
spellingShingle Phase I Studies
Chiu, Joanne W.
Hotte, Sebastien J.
Kollmannsberger, Christian K.
Renouf, Daniel J.
Cescon, David W.
Hedley, David
Chow, Sue
Moscow, Jeffrey
Chen, Zhuo
Perry, Meghan
Diaz-Padilla, Ivan
Tan, David
Hirte, Hal
McWhirter, Elaine
Chen, Helen
Siu, Lillian L.
Bedard, Philippe L.
A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI♯9041)
title A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI♯9041)
title_full A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI♯9041)
title_fullStr A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI♯9041)
title_full_unstemmed A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI♯9041)
title_short A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI♯9041)
title_sort phase i trial of ang1/2-tie2 inhibitor trebaninib (amg386) and temsirolimus in advanced solid tumors (pjc008/nci♯9041)
topic Phase I Studies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718956/
https://www.ncbi.nlm.nih.gov/pubmed/26686201
http://dx.doi.org/10.1007/s10637-015-0313-8
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