title: A Phase 2 Study of the Hsp90 Inhibitor AUY922 as Treatment for Patients with Refractory Gastrointestinal Stromal Tumors.
abstract: BACKGROUND
  AUY922 is an inhibitor of heat shock protein 90 (Hsp90). Hsp90 inhibitors induce kit degradation in preclinical gastrointestinal stromal tumor (GIST) models. This trial was designed to determine the progression-free survival (PFS) of patients with GIST refractory to or intolerant of imatinib and sunitinib.
  
  
  METHODS
  Eligible patients received AUY922 70 mg/mg(2) by intravenous (IV) infusion on days 1, 8, and 15 of 21-day cycles. Treatment continued until progression or unacceptable toxicity.
  
  
  RESULTS
  Between December 2011 and January 2015, 25 patients were enrolled (median age, 63 years; 56% male) and received a median of 2 cycles (range: 1-12) of AUY922 treatment. Thirty-four patients were planned, but enrollment was stopped early due to slow accrual. Median PFS was 3.9 months (95% CI: 2.5, 5.3) and median OS was 8.5 months (95% CI: 5.2, 16.7). Radiographic response was evaluated in 21 patients; one patient achieved PR (4%) with another 15 having best response of stable disease (60%). The most common treatment-related adverse event was diarrhea (60% all grades). Reversible ocular toxicities that resulted in drug hold (24%) or reduction (8%) were also observed.
  
  
  CONCLUSIONS
  AUY922 produced a median PFS which compares favorably to historical controls of placebo (6 weeks) for patients refractory to treatment with imatinib. While diarrhea and ocular toxicities were common, the majority of patients received treatment until disease progression.
authors.affiliation: a Sarah Cannon Research Institute , Nashville , TN , USA.|b Tennessee Oncology , PLLC , Nashville , TN , USA.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.affiliation: a Sarah Cannon Research Institute , Nashville , TN , USA.|b Tennessee Oncology , PLLC , Nashville , TN , USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Bauer
authors.affiliation: a Sarah Cannon Research Institute , Nashville , TN , USA.|b Tennessee Oncology , PLLC , Nashville , TN , USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Lamar
authors.affiliation: a Sarah Cannon Research Institute , Nashville , TN , USA.|b Tennessee Oncology , PLLC , Nashville , TN , USA.
authors.forename: Mathew
authors.initials: M
authors.lastname: Joseph
authors.affiliation: a Sarah Cannon Research Institute , Nashville , TN , USA.|b Tennessee Oncology , PLLC , Nashville , TN , USA.
authors.forename: William
authors.initials: W
authors.lastname: Penley
authors.affiliation: a Sarah Cannon Research Institute , Nashville , TN , USA.|b Tennessee Oncology , PLLC , Nashville , TN , USA.
authors.forename: Dana S
authors.initials: DS
authors.lastname: Thompson
authors.affiliation: a Sarah Cannon Research Institute , Nashville , TN , USA.|b Tennessee Oncology , PLLC , Nashville , TN , USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Spigel
authors.affiliation: c Woodlands Medical Specialists , Pensacola , FL , USA.
authors.forename: Rami
authors.initials: R
authors.lastname: Owera
authors.affiliation: a Sarah Cannon Research Institute , Nashville , TN , USA.
authors.forename: Cassie M
authors.initials: CM
authors.lastname: Lane
authors.affiliation: a Sarah Cannon Research Institute , Nashville , TN , USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Earwood
authors.affiliation: a Sarah Cannon Research Institute , Nashville , TN , USA.|b Tennessee Oncology , PLLC , Nashville , TN , USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012118:Resorcinols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019233:Retreatment; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D012118:Resorcinols
keywords: AUY922; GIST; Heat shock protein 90; Hsp90