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Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma
BACKGROUND: This study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of the first-in-class dual mammalian target of rapamycin complex (mTORC)1/mTORC2 inhibitor, AZD8055. METHODS: Patients with advanced solid malignancies or lymphomas were recruited into this phase I, open-...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461162/ https://www.ncbi.nlm.nih.gov/pubmed/22935583 http://dx.doi.org/10.1038/bjc.2012.368 |
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author | Naing, A Aghajanian, C Raymond, E Olmos, D Schwartz, G Oelmann, E Grinsted, L Burke, W Taylor, R Kaye, S Kurzrock, R Banerji, U |
author_facet | Naing, A Aghajanian, C Raymond, E Olmos, D Schwartz, G Oelmann, E Grinsted, L Burke, W Taylor, R Kaye, S Kurzrock, R Banerji, U |
author_sort | Naing, A |
collection | PubMed |
description | BACKGROUND: This study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of the first-in-class dual mammalian target of rapamycin complex (mTORC)1/mTORC2 inhibitor, AZD8055. METHODS: Patients with advanced solid malignancies or lymphomas were recruited into this phase I, open-label, dose-escalation study of AZD8055 starting at 10 mg twice-daily oral dosing (BID). RESULTS: Forty-nine patients received AZD8055. Dose-limiting toxicities were reported at 40 mg (n=1), 90 mg (n=1) and 120 mg (n=3) BID; all were grade 3 rises in transaminases, reversible in all patients, apart from one who had liver metastases. The maximum tolerated dose was defined as 90 mg BID. The most frequent adverse events assessed to be related to AZD8055 were increased alanine aminotransferase (22%), increased aspartate aminotransferase (22%) and fatigue (16%). AZD8055 was rapidly absorbed (median t(max) ∼0.5 h) and exposure increased with increasing doses. Seven patients had stable disease for ⩾4 months. Partial metabolic responses, assessed by fluorodeoxyglucose positron emission tomography, were observed at ⩾40 mg BID (n=8 at day 35). CONCLUSION: The maximum tolerated dose for AZD8055 is 90 mg BID. Apart from elevated transaminases, which occurred at most dose levels, the drug had an acceptable toxicity profile; however, no RECIST responses were seen. |
format | Online Article Text |
id | pubmed-3461162 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-34611622013-09-25 Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma Naing, A Aghajanian, C Raymond, E Olmos, D Schwartz, G Oelmann, E Grinsted, L Burke, W Taylor, R Kaye, S Kurzrock, R Banerji, U Br J Cancer Translational Therapeutics BACKGROUND: This study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of the first-in-class dual mammalian target of rapamycin complex (mTORC)1/mTORC2 inhibitor, AZD8055. METHODS: Patients with advanced solid malignancies or lymphomas were recruited into this phase I, open-label, dose-escalation study of AZD8055 starting at 10 mg twice-daily oral dosing (BID). RESULTS: Forty-nine patients received AZD8055. Dose-limiting toxicities were reported at 40 mg (n=1), 90 mg (n=1) and 120 mg (n=3) BID; all were grade 3 rises in transaminases, reversible in all patients, apart from one who had liver metastases. The maximum tolerated dose was defined as 90 mg BID. The most frequent adverse events assessed to be related to AZD8055 were increased alanine aminotransferase (22%), increased aspartate aminotransferase (22%) and fatigue (16%). AZD8055 was rapidly absorbed (median t(max) ∼0.5 h) and exposure increased with increasing doses. Seven patients had stable disease for ⩾4 months. Partial metabolic responses, assessed by fluorodeoxyglucose positron emission tomography, were observed at ⩾40 mg BID (n=8 at day 35). CONCLUSION: The maximum tolerated dose for AZD8055 is 90 mg BID. Apart from elevated transaminases, which occurred at most dose levels, the drug had an acceptable toxicity profile; however, no RECIST responses were seen. Nature Publishing Group 2012-09-25 2012-08-30 /pmc/articles/PMC3461162/ /pubmed/22935583 http://dx.doi.org/10.1038/bjc.2012.368 Text en Copyright © 2012 Cancer Research UK https://creativecommons.org/licenses/by-nc-sa/3.0/From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/ |
spellingShingle | Translational Therapeutics Naing, A Aghajanian, C Raymond, E Olmos, D Schwartz, G Oelmann, E Grinsted, L Burke, W Taylor, R Kaye, S Kurzrock, R Banerji, U Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma |
title | Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma |
title_full | Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma |
title_fullStr | Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma |
title_full_unstemmed | Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma |
title_short | Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma |
title_sort | safety, tolerability, pharmacokinetics and pharmacodynamics of azd8055 in advanced solid tumours and lymphoma |
topic | Translational Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461162/ https://www.ncbi.nlm.nih.gov/pubmed/22935583 http://dx.doi.org/10.1038/bjc.2012.368 |
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