title: Phase I study of the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat in advanced renal cell carcinoma and other solid tumors.
abstract: BACKGROUND
  Drugs inhibiting the mammalian target of rapamycin (mTOR) are approved in the treatment of renal cell carcinoma (RCC), but resistance inevitably emerges. Proposed escape pathways include increased phosphorylation of Akt, which can be down regulated by histone deacetylase (HDAC) inhibitors. We hypothesized that co-treatment with the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat may abrogate resistance in RCC.
  
  
  METHODS
  This phase 1 study evaluated the co-administration of ridaforolimus and vorinostat in patients with advanced solid tumors. The primary objective was to determine the maximum tolerated dose (MTD) in RCC patients. Although all solid tumors were allowed, prior cytotoxic chemotherapy was limited to 1 regimen. Using a modified 3 + 3 dose escalation design, various dose combinations were tested concurrently in separate cohorts. Efficacy was a secondary endpoint.
  
  
  RESULTS
  Fifteen patients were treated at one of three dose levels, thirteen with RCC (10 clear cell, 3 papillary). Dosing was limited by thrombocytopenia. The MTD was determined to be ridaforolimus 20 mg daily days 1-5 with vorinostat 100 mg BID days 1-3 weekly, however late onset thrombocytopenia led to a lower recommended phase II dose: ridaforolimus 20 mg daily days 1-5 with vorinostat 100 mg daily days 1-3 weekly. Two patients, both with papillary RCC, maintained disease control for 54 and 80 weeks, respectively.
  
  
  CONCLUSIONS
  The combination of ridaforolimus and vorinostat was tolerable at the recommended phase II dose. Two patients with papillary RCC experienced prolonged disease stabilization, thus further study of combined HDAC and mTOR inhibition in this population is warranted.
authors.affiliation: Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Zibelman
authors.affiliation: Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA.
authors.forename: Yu-Ning
authors.initials: YN
authors.lastname: Wong
authors.affiliation: Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA.
authors.forename: Karthik
authors.initials: K
authors.lastname: Devarajan
authors.affiliation: Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA.
authors.forename: Lois
authors.initials: L
authors.lastname: Malizzia
authors.affiliation: Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA.
authors.forename: Alycia
authors.initials: A
authors.lastname: Corrigan
authors.affiliation: Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Olszanski
authors.affiliation: Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA.
authors.forename: Crystal S
authors.initials: CS
authors.lastname: Denlinger
authors.affiliation: Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Roethke
authors.affiliation: Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA.
authors.forename: Colleen H
authors.initials: CH
authors.lastname: Tetzlaff
authors.affiliation: Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA. elizabeth.plimack@fccc.edu.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Plimack
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C515074:ridaforolimus; D000077337:Vorinostat; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: HDAC inhibition; Papillary; Renal cell carcinoma; mTOR inhibition; mTOR resistance