Cargando…

Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy

Preclinical models suggest that histone deacetylase (HDAC) and mammalian target of rapamycin (mTOR) inhibitors have synergistic anticancer activity. We designed a phase I study to determine the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs...

Descripción completa

Detalles Bibliográficos
Autores principales: Park, Haeseong, Garrido-Laguna, Ignacio, Naing, Aung, Fu, Siqing, Falchook, Gerald S., Piha-Paul, Sarina A., Wheler, Jennifer J., Hong, David S., Tsimberidou, Apostolia M., Subbiah, Vivek, Zinner, Ralph G., Kaseb, Ahmed O., Patel, Shreyaskumar, Fanale, Michelle A., Velez-Bravo, Vivianne M., Meric-Bernstam, Funda, Kurzrock, Razelle, Janku, Filip
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341894/
https://www.ncbi.nlm.nih.gov/pubmed/27589687
http://dx.doi.org/10.18632/oncotarget.11750
_version_ 1782513056600817664
author Park, Haeseong
Garrido-Laguna, Ignacio
Naing, Aung
Fu, Siqing
Falchook, Gerald S.
Piha-Paul, Sarina A.
Wheler, Jennifer J.
Hong, David S.
Tsimberidou, Apostolia M.
Subbiah, Vivek
Zinner, Ralph G.
Kaseb, Ahmed O.
Patel, Shreyaskumar
Fanale, Michelle A.
Velez-Bravo, Vivianne M.
Meric-Bernstam, Funda
Kurzrock, Razelle
Janku, Filip
author_facet Park, Haeseong
Garrido-Laguna, Ignacio
Naing, Aung
Fu, Siqing
Falchook, Gerald S.
Piha-Paul, Sarina A.
Wheler, Jennifer J.
Hong, David S.
Tsimberidou, Apostolia M.
Subbiah, Vivek
Zinner, Ralph G.
Kaseb, Ahmed O.
Patel, Shreyaskumar
Fanale, Michelle A.
Velez-Bravo, Vivianne M.
Meric-Bernstam, Funda
Kurzrock, Razelle
Janku, Filip
author_sort Park, Haeseong
collection PubMed
description Preclinical models suggest that histone deacetylase (HDAC) and mammalian target of rapamycin (mTOR) inhibitors have synergistic anticancer activity. We designed a phase I study to determine the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of combined mTOR inhibitor sirolimus (1 mg-5 mg PO daily) and HDAC inhibitor vorinostat (100 mg-400 mg PO daily) in patients with advanced cancer. Seventy patients were enrolled and 46 (66%) were evaluable for DLT assessment since they completed cycle 1 without dose modification unless they had DLT. DLTs comprised grade 4 thrombocytopenia (n = 6) and grade 3 mucositis (n = 1). Sirolimus 4 mg and vorinostat 300 mg was declared RP2D because MTD with sirolimus 5 mg caused significant thrombocytopenia. The grade 3 and 4 drug-related toxic effects (including DLTs) were thrombocytopenia (31%), neutropenia (8%), anemia (7%), fatigue (3%), mucositis (1%), diarrhea (1%), and hyperglycemia (1%). Of the 70 patients, 35 (50%) required dose interruption or modification and 61 were evaluable for response. Partial responses were observed in refractory Hodgkin lymphoma (−78%) and perivascular epithelioid tumor (−54%), and stable disease in hepatocellular carcinoma and fibromyxoid sarcoma. In conclusion, the combination of sirolimus and vorinostat was feasible, with thrombocytopenia as the main DLT. Preliminary anticancer activity was observed in patients with refractory Hodgkin lymphoma, perivascular epithelioid tumor, and hepatocellular carcinoma.
format Online
Article
Text
id pubmed-5341894
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-53418942017-03-23 Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy Park, Haeseong Garrido-Laguna, Ignacio Naing, Aung Fu, Siqing Falchook, Gerald S. Piha-Paul, Sarina A. Wheler, Jennifer J. Hong, David S. Tsimberidou, Apostolia M. Subbiah, Vivek Zinner, Ralph G. Kaseb, Ahmed O. Patel, Shreyaskumar Fanale, Michelle A. Velez-Bravo, Vivianne M. Meric-Bernstam, Funda Kurzrock, Razelle Janku, Filip Oncotarget Clinical Research Paper Preclinical models suggest that histone deacetylase (HDAC) and mammalian target of rapamycin (mTOR) inhibitors have synergistic anticancer activity. We designed a phase I study to determine the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of combined mTOR inhibitor sirolimus (1 mg-5 mg PO daily) and HDAC inhibitor vorinostat (100 mg-400 mg PO daily) in patients with advanced cancer. Seventy patients were enrolled and 46 (66%) were evaluable for DLT assessment since they completed cycle 1 without dose modification unless they had DLT. DLTs comprised grade 4 thrombocytopenia (n = 6) and grade 3 mucositis (n = 1). Sirolimus 4 mg and vorinostat 300 mg was declared RP2D because MTD with sirolimus 5 mg caused significant thrombocytopenia. The grade 3 and 4 drug-related toxic effects (including DLTs) were thrombocytopenia (31%), neutropenia (8%), anemia (7%), fatigue (3%), mucositis (1%), diarrhea (1%), and hyperglycemia (1%). Of the 70 patients, 35 (50%) required dose interruption or modification and 61 were evaluable for response. Partial responses were observed in refractory Hodgkin lymphoma (−78%) and perivascular epithelioid tumor (−54%), and stable disease in hepatocellular carcinoma and fibromyxoid sarcoma. In conclusion, the combination of sirolimus and vorinostat was feasible, with thrombocytopenia as the main DLT. Preliminary anticancer activity was observed in patients with refractory Hodgkin lymphoma, perivascular epithelioid tumor, and hepatocellular carcinoma. Impact Journals LLC 2016-08-31 /pmc/articles/PMC5341894/ /pubmed/27589687 http://dx.doi.org/10.18632/oncotarget.11750 Text en Copyright: © 2016 Park et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Clinical Research Paper
Park, Haeseong
Garrido-Laguna, Ignacio
Naing, Aung
Fu, Siqing
Falchook, Gerald S.
Piha-Paul, Sarina A.
Wheler, Jennifer J.
Hong, David S.
Tsimberidou, Apostolia M.
Subbiah, Vivek
Zinner, Ralph G.
Kaseb, Ahmed O.
Patel, Shreyaskumar
Fanale, Michelle A.
Velez-Bravo, Vivianne M.
Meric-Bernstam, Funda
Kurzrock, Razelle
Janku, Filip
Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy
title Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy
title_full Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy
title_fullStr Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy
title_full_unstemmed Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy
title_short Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy
title_sort phase i dose-escalation study of the mtor inhibitor sirolimus and the hdac inhibitor vorinostat in patients with advanced malignancy
topic Clinical Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341894/
https://www.ncbi.nlm.nih.gov/pubmed/27589687
http://dx.doi.org/10.18632/oncotarget.11750
work_keys_str_mv AT parkhaeseong phaseidoseescalationstudyofthemtorinhibitorsirolimusandthehdacinhibitorvorinostatinpatientswithadvancedmalignancy
AT garridolagunaignacio phaseidoseescalationstudyofthemtorinhibitorsirolimusandthehdacinhibitorvorinostatinpatientswithadvancedmalignancy
AT naingaung phaseidoseescalationstudyofthemtorinhibitorsirolimusandthehdacinhibitorvorinostatinpatientswithadvancedmalignancy
AT fusiqing phaseidoseescalationstudyofthemtorinhibitorsirolimusandthehdacinhibitorvorinostatinpatientswithadvancedmalignancy
AT falchookgeralds phaseidoseescalationstudyofthemtorinhibitorsirolimusandthehdacinhibitorvorinostatinpatientswithadvancedmalignancy
AT pihapaulsarinaa phaseidoseescalationstudyofthemtorinhibitorsirolimusandthehdacinhibitorvorinostatinpatientswithadvancedmalignancy
AT whelerjenniferj phaseidoseescalationstudyofthemtorinhibitorsirolimusandthehdacinhibitorvorinostatinpatientswithadvancedmalignancy
AT hongdavids phaseidoseescalationstudyofthemtorinhibitorsirolimusandthehdacinhibitorvorinostatinpatientswithadvancedmalignancy
AT tsimberidouapostoliam phaseidoseescalationstudyofthemtorinhibitorsirolimusandthehdacinhibitorvorinostatinpatientswithadvancedmalignancy
AT subbiahvivek phaseidoseescalationstudyofthemtorinhibitorsirolimusandthehdacinhibitorvorinostatinpatientswithadvancedmalignancy
AT zinnerralphg phaseidoseescalationstudyofthemtorinhibitorsirolimusandthehdacinhibitorvorinostatinpatientswithadvancedmalignancy
AT kasebahmedo phaseidoseescalationstudyofthemtorinhibitorsirolimusandthehdacinhibitorvorinostatinpatientswithadvancedmalignancy
AT patelshreyaskumar phaseidoseescalationstudyofthemtorinhibitorsirolimusandthehdacinhibitorvorinostatinpatientswithadvancedmalignancy
AT fanalemichellea phaseidoseescalationstudyofthemtorinhibitorsirolimusandthehdacinhibitorvorinostatinpatientswithadvancedmalignancy
AT velezbravoviviannem phaseidoseescalationstudyofthemtorinhibitorsirolimusandthehdacinhibitorvorinostatinpatientswithadvancedmalignancy
AT mericbernstamfunda phaseidoseescalationstudyofthemtorinhibitorsirolimusandthehdacinhibitorvorinostatinpatientswithadvancedmalignancy
AT kurzrockrazelle phaseidoseescalationstudyofthemtorinhibitorsirolimusandthehdacinhibitorvorinostatinpatientswithadvancedmalignancy
AT jankufilip phaseidoseescalationstudyofthemtorinhibitorsirolimusandthehdacinhibitorvorinostatinpatientswithadvancedmalignancy