title: Phase I study of vorinostat (suberoylanilide hydroxamic acid, NSC 701852) in combination with docetaxel in patients with advanced and relapsed solid malignancies.
abstract: BACKGROUND
  Vorinostat is an inhibitor of histone deacetylase 6, which acetylates tubulin and stabilizes microtubules. Since taxanes also stabilize microtubules, we hypothesized that the administration of vorinostat followed by docetaxel should result in synergistic cytotoxicity. We conducted a phase I trial to determine the dose level of vorinostat plus docetaxel that would result in dose-limiting toxicity (DLT) in ≤30% of patients.
  
  
  METHODS
  Eligible patients had castration-resistant prostate cancer (CRPC) or relapsed urothelial or non-small-cell lung cancer (NSCLC) after ≥1 prior chemotherapy regimen not containing docetaxel, performance status of 0-2, and adequate organ function. Vorinostat was given orally for 14 days beginning on day 1 of a 21-day cycle, with docetaxel given intravenously over 1 h on day 4. The time-to-event continuous reassessment method (TITE-CRM) guided dose escalation. Dose levels (DL) -1, 0, 1 and 2 corresponded to vorinostat 100, 100, 200 and 200 mg plus docetaxel 50, 60, 60, and 75 mg/m(2), respectively. Pharmacokinetic studies were performed on days 1 and 4 of cycle 1.
  
  
  RESULTS
  Twelve patients were enrolled: median age 65 years (range 49-74); 9 male, 3 female; 4 CRPC, 5 urothelial, 3 NSCLC. The median number of cycles administered was 2. Two patients were treated at DL -1, 4 at DL 0, 5 at DL 1 and 1 at DL 2. Five DLTs occurred in 5 patients: neutropenic fever/sepsis (2), anaphylactic reaction (1), myocardial infarction (1) and gastrointestinal bleed (1). Other toxicities included grade 3/4 neutropenia (4), peripheral neuropathy (1), and gastrointestinal bleed (n = 1). The estimated probability of DLT for DL -1 was 0.32 (90% posterior probability interval [PI], 0.11 to 0.53) for DL 0, 0.38 (90% PI, 0.16 to 0.58) and for DL 1, 0.43 (90% PI, 0.23 to 0.64). The trial was stopped due to excessive toxicity. No responses were noted.
  
  
  CONCLUSIONS
  The combination of vorinostat and docetaxel was poorly tolerated with excessive DLTs that required early study termination. No responses were identified. Vorinostat and docetaxel pharmacokinetics were comparable to previous reports in the literature, without obvious drug-drug interactions.
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, Weill Cornell Medical College, 525 East 68th Street, 3rd floor, New York, NY 10065, USA. bjs2004@med.cornell.edu
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Schneider
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Kalemkerian
authors.forename: Deborah
authors.initials: D
authors.lastname: Bradley
authors.forename: David C
authors.initials: DC
authors.lastname: Smith
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: Stephanie
authors.initials: S
authors.lastname: Daignault
authors.forename: Rodney
authors.initials: R
authors.lastname: Dunn
authors.forename: Maha
authors.initials: M
authors.lastname: Hussain
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000556:secondary; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage; D013997:Time Factors; D016896:Treatment Outcome; D050257:Tubulin Modulators / Q000008:administration & dosage; D014571:Urologic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D043823:Taxoids; D050257:Tubulin Modulators; D000077143:Docetaxel; D000077337:Vorinostat