title: A phase I and pharmacokinetic study of ganetespib (STA-9090) in advanced hepatocellular carcinoma.
abstract: BACKGROUND
  Ganetespib (STA-9090) is an Hsp90 inhibitor that downregulates VEGFR, c-MET, HER2, IGF-IR, EGFR, and other Hsp90 client proteins involved in hepatocarcinogenesis, thereby making it an attractive therapy for HCC. This Phase I study was performed to establish the safety, tolerability, recommended Phase 2 dose (RP2D), and preliminary clinical activity of ganetespib in previously treated patients with advanced HCC.
  
  
  METHODS
  Patients with advanced HCC, Child-Pugh A cirrhosis, progression on or intolerance to sorafenib, and ECOG PS ≤ 1 were enrolled in a standard 3x3 dose escalation study at doses of 100 mg/m(2), 150 mg/m(2), and 200 mg/m(2) IV given on days 1, 8, and 15 of each 28-day cycle. Objective response by RECIST version 1.1 criteria was evaluated by CT/MRI every 8 weeks.
  
  
  RESULTS
  Fourteen patients were enrolled in this trial and received at least one dose of the study drug. Of the 14 patients: median age, 57 years old; male 71 %; Asian 36 %; HCC etiology (HBV 36 %, HCV 43 %, Hemachromatosis 7 %, unknown 21 %); Child Pugh Class (A 93 %, B 7 %); median number of prior treatments 2; median baseline AFP 70.1 ng/mL. The RP2D was determined to be 200 mg/m(2). The most commonly seen AEs were diarrhea (93 %), fatigue (71 %), AST elevation (64 %), and hyperglycemia (64 %). The most common Gr 3/4 AEs were hyperglycemia (21 %) and lipasemia (21 %). One (7 %) patient had a fatal AE, septic shock, within 30 days of receiving the study drug. One dose-limiting toxicity, grade 3 lipasemia, was observed at the 100 mg/m(2) dose. Pharmacokinetics studies showed a t1/2, CL, Tmax, and Vss of 6.45 h, 48.28 L/h (25.56 L/h/m(2)), 0.76 h, and 191 L (100.4 L/m(2)), respectively. No objective responses were seen; one patient (7 %) had stable disease at 16 weeks. Median time to progression was 1.8 months, and median overall survival was 7.2 months.
  
  
  CONCLUSIONS
  Ganetespib had a manageable safety profile in patients with advanced HCC who had progressed on at least one line of systemic therapy. The pharmacokinetic profile showed that ganetespib exposure in patients with mild hepatic dysfunction is similar to that seen in patients with normal liver function. Ganetespib showed limited clinical benefit in patients with advanced HCC in this phase I trial.
authors.affiliation: Massachusetts General Hospital Cancer Center, 55 Fruit Street, LH/PB 220, Boston, MA, 02114, USA, lgoyal@partners.org.
authors.forename: Lipika
authors.initials: L
authors.lastname: Goyal
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Wadlow
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Blaszkowsky
authors.forename: Brian M
authors.initials: BM
authors.lastname: Wolpin
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Abrams
authors.forename: Nadine Jackson
authors.initials: NJ
authors.lastname: McCleary
authors.forename: Susan
authors.initials: S
authors.lastname: Sheehan
authors.forename: Eamala
authors.initials: E
authors.lastname: Sundaram
authors.forename: Michael D
authors.initials: MD
authors.lastname: Karol
authors.forename: John
authors.initials: J
authors.lastname: Chen
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014230:Triazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D018841:HSP90 Heat-Shock Proteins; C533237:STA 9090; D014230:Triazoles