Clinical Research Papers:
Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy
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Haeseong Park1,2, Ignacio Garrido-Laguna3, Aung Naing1, Siqing Fu1, Gerald S. Falchook1,4, Sarina A. Piha-Paul1, Jennifer J. Wheler1, David S. Hong1, Apostolia M. Tsimberidou1, Vivek Subbiah1, Ralph G. Zinner1,5, Ahmed O. Kaseb6, Shreyaskumar Patel7, Michelle A. Fanale8, Vivianne M. Velez-Bravo1, Funda Meric-Bernstam1, Razelle Kurzrock9 and Filip Janku1
1 Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2 Department of Internal Medicine (Division of Oncology), Washington University School of Medicine, St. Louis, MO, USA
3 Department of Internal Medicine (Division of Oncology), Huntsman Cancer Institute and University of Utah School of Medicine, Salt Lake City, UT, USA
4 Sarah Cannon Research Institute at HealthONE, Denver, CO, USA
5 Medical Oncology, Thomas Jefferson University and Jefferson University Hospitals, Philadelphia, PA, USA
6 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
7 Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
8 Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
9 Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, San Diego, CA, USA
Filip Janku, email:
Keywords: phase I, sirolimus, vorinostat, mTOR, HDAC
Received: May 20, 2016 Accepted: July 02, 2016 Published: August 31, 2016
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.
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