title: Phase 1/1B trial of the heat shock protein 90 inhibitor NVP-AUY922 as monotherapy or in combination with bortezomib in patients with relapsed or refractory multiple myeloma.
abstract: BACKGROUND
  NVP-AUY922 (AUY; Luminespib) with or without bortezomib showed preclinical activity against multiple myeloma (MM) cells. This phase 1/1B study assessed NVP-AUY922 alone and with bortezomib in patients with relapsed or refractory MM.
  
  
  METHODS
  Dose escalation was guided by an adaptive Bayesian logistic regression model. In phase 1, patients who progressed after 2 to 4 prior therapies received NVP-AUY922 intravenously once weekly. In phase 1B, patients who progressed after 2 or fewer prior therapies received NVP-AUY922 plus bortezomib. The primary objective was to determine the maximum tolerated dose (MTD) of NVP-AUY922.
  
  
  RESULTS
  Twenty-four patients received NVP-AUY922 monotherapy at doses of 8 to 70 mg/m(2) . One dose-limiting toxicity (DLT) was observed (grade 3 blurred vision at 70 mg/m(2) ); no MTD was reached. The recommended phase 2 dose was 70 mg/m(2) . The most frequent drug-related adverse events (AEs) were diarrhea, nausea, and ocular toxicities. Grade 3/4 AEs were uncommon (<10%). Eight patients discontinued treatment because of AEs; 5 had ocular toxicities (≥45 mg/m(2) ). The best response was stable disease in 66.7% of the patients. There were no partial or complete responses. Five patients received NVP-AUY922 (which was started at 50 mg/m(2) ) plus bortezomib (1.3 mg/m(2) ). Three of these patients experienced DLT. No further dose escalation was performed; the MTD for NVP-AUY922 plus bortezomib was not established.
  
  
  CONCLUSIONS
  This study showed disease stabilization with NVP-AUY922 in patients with relapsed or refractory MM. The MTD for NVP-AUY922 was not reached, but reversible ocular toxicity has been reported at high dose levels. Bortezomib at the standard recommended dose plus NVP-AUY922 was not tolerated.
authors: Comprehensive Cancer Center Mainfranken, University Hospital of Wuerzburg, Wuerzburg, Germany.
authors: Ruth
authors: R
authors: Seggewiss-Bernhardt
authors: Department of Internal Medicine II, University Hospital of Wuerzburg, Wuerzburg, Germany.
authors: Ralf C
authors: RC
authors: Bargou
authors: Department of Hematology, Singapore General Hospital, Singapore.
authors: Yeow Tee
authors: YT
authors: Goh
authors: Department of Hematology, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors: A Keith
authors: AK
authors: Stewart
authors: Department of Clinical Hematology, Alfred Health-Monash University, Melbourne, Australia.
authors: Andrew
authors: A
authors: Spencer
authors: Department of Hematology, Princesa University Hospital, Madrid, Spain.
authors: Adrian
authors: A
authors: Alegre
authors: Department of Hematology, August Pi i Sunyer Institute for Biomedical Research, Barcelona, Spain.
authors: Joan
authors: J
authors: Bladé
authors: Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt, Germany.
authors: Oliver G
authors: OG
authors: Ottmann
authors: Department of Oncology, Novartis Pharma AG, Basel, Switzerland.
authors: Cristina
authors: C
authors: Fernandez-Ibarra
authors: Department of Oncology, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
authors: Hong
authors: H
authors: Lu
authors: Department of Oncology, Novartis Pharma AG, Basel, Switzerland.
authors: Scott
authors: S
authors: Pain
authors: Department of Oncology, Novartis Pharma AG, Basel, Switzerland.
authors: Mikhail
authors: M
authors: Akimov
authors: Department of Hematology, Houston Methodist Cancer Center, Houston, Texas, USA.
authors: Swaminathan Padmanabhan
authors: SP
authors: Iyer
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000069286:Bortezomib / Q000008:administration & dosage; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012118:Resorcinols / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D012118:Resorcinols; D000069286:Bortezomib
keywords: AUY922; bortezomib; heat shock protein 90; heat shock protein 90 inhibitors; proteasome inhibitor; relapsed or refractory multiple myeloma