title: Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy.
abstract: 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.
authors: 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.|Department of Internal Medicine (Division of Oncology), Washington University School of Medicine, St. Louis, MO, USA.
authors: Haeseong
authors: H
authors: Park
authors: Department of Internal Medicine (Division of Oncology), Huntsman Cancer Institute and University of Utah School of Medicine, Salt Lake City, UT, USA.
authors: Ignacio
authors: I
authors: Garrido-Laguna
authors: 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.
authors: Aung
authors: A
authors: Naing
authors: 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.
authors: Siqing
authors: S
authors: Fu
authors: 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.|Sarah Cannon Research Institute at HealthONE, Denver, CO, USA.
authors: Gerald S
authors: GS
authors: Falchook
authors: 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.
authors: Sarina A
authors: SA
authors: Piha-Paul
authors: 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.
authors: Jennifer J
authors: JJ
authors: Wheler
authors: 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.
authors: David S
authors: DS
authors: Hong
authors: 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.
authors: Apostolia M
authors: AM
authors: Tsimberidou
authors: 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.
authors: Vivek
authors: V
authors: Subbiah
authors: 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.|Medical Oncology, Thomas Jefferson University and Jefferson University Hospitals, Philadelphia, PA, USA.
authors: Ralph G
authors: RG
authors: Zinner
authors: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Ahmed O
authors: AO
authors: Kaseb
authors: Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Shreyaskumar
authors: S
authors: Patel
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Michelle A
authors: MA
authors: Fanale
authors: 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.
authors: Vivianne M
authors: VM
authors: Velez-Bravo
authors: 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.
authors: Funda
authors: F
authors: Meric-Bernstam
authors: Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, San Diego, CA, USA.
authors: Razelle
authors: R
authors: Kurzrock
authors: 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.
authors: Filip
authors: F
authors: Janku
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077337:Vorinostat; D055815:Young Adult
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: HDAC; mTOR; phase I; sirolimus; vorinostat