title: A phase I study of sorafenib and vorinostat in patients with advanced solid tumors with expanded cohorts in renal cell carcinoma and non-small cell lung cancer.
abstract: BACKGROUND
  This phase I study evaluated the safety, tolerability and preliminary efficacy of sorafenib combined with vorinostat in patients with solid tumors.
  
  
  METHODS
  Patients were treated with sorafenib 400 mg po bid daily and vorinostat 200-400 mg po days 1-14 of a 21 day cycle to establish the recommended phase II dose (RP2D). The tolerability and efficacy of the RP2D was further tested in two cohorts of 6-12 patients each with advanced RCC and NSCLC.
  
  
  RESULTS
  17 patients were treated in the dose escalation phase that established the RP2D at sorafenib 400 mg po bid daily, vorinostat 300 mg po days 1-14. Dose limiting toxicities (DLT) included intolerable grade 2 hand-foot syndrome and multiple grade 1 toxicities causing dose interruption for more than 14 days. Despite good tolerance in the all-comers population, the RP2D was poorly tolerated in the RCC and NSCLC cohorts with the majority being unable to finish 2 full cycles of therapy. Although there were no confirmed responses, 1 patient each with NSCLC adenocarcinoma and renal sarcoma had unconfirmed partial responses and 5 of 8 patients with RCC having durable minor responses (11-26 %), including 2 who were on treatment for nearly a year.
  
  
  CONCLUSIONS
  Although tolerable in other tumor types, sorafenib 400 mg po bid with vorinostat 300 mg po daily days 1-14 of a 21-day cycle is not tolerable without dose reductions/delays in RCC and NSCLC patients. These patients may require lower doses than the RP2D explored within this study. No confirmed responses were seen but minor responses particularly in RCC were observed.
authors.affiliation: University of Colorado Cancer Center, Aurora, CO, USA. adasari@mdanderson.org
authors.forename: A
authors.initials: A
authors.lastname: Dasari
authors.forename: L
authors.initials: L
authors.lastname: Gore
authors.forename: W A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: S
authors.initials: S
authors.lastname: Diab
authors.forename: A
authors.initials: A
authors.lastname: Jimeno
authors.forename: C D
authors.initials: CD
authors.lastname: Weekes
authors.forename: K D
authors.initials: KD
authors.lastname: Lewis
authors.forename: H A
authors.initials: HA
authors.lastname: Drabkin
authors.forename: T W
authors.initials: TW
authors.lastname: Flaig
authors.forename: D R
authors.initials: DR
authors.lastname: Camidge
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D000077157:Sorafenib; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077337:Vorinostat; D000077157:Sorafenib