PMID- 25809731
OWN - NLM
STAT- MEDLINE
DCOM- 20160831
LR  - 20220410
IS  - 1097-0142 (Electronic)
IS  - 0008-543X (Linking)
VI  - 121
IP  - 13
DP  - 2015 Jul 1
TI  - 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.
PG  - 2185-92
LID - 10.1002/cncr.29339 [doi]
AB  - 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.
CI  - (c) 2015 American Cancer Society.
FAU - Seggewiss-Bernhardt, Ruth
AU  - Seggewiss-Bernhardt R
AD  - Comprehensive Cancer Center Mainfranken, University Hospital of Wuerzburg, 
      Wuerzburg, Germany.
FAU - Bargou, Ralf C
AU  - Bargou RC
AD  - Department of Internal Medicine II, University Hospital of Wuerzburg, Wuerzburg, 
      Germany.
FAU - Goh, Yeow Tee
AU  - Goh YT
AD  - Department of Hematology, Singapore General Hospital, Singapore.
FAU - Stewart, A Keith
AU  - Stewart AK
AD  - Department of Hematology, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
FAU - Spencer, Andrew
AU  - Spencer A
AD  - Department of Clinical Hematology, Alfred Health-Monash University, Melbourne, 
      Australia.
FAU - Alegre, Adrian
AU  - Alegre A
AD  - Department of Hematology, Princesa University Hospital, Madrid, Spain.
FAU - Blade, Joan
AU  - Blade J
AD  - Department of Hematology, August Pi i Sunyer Institute for Biomedical Research, 
      Barcelona, Spain.
FAU - Ottmann, Oliver G
AU  - Ottmann OG
AD  - Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt, 
      Germany.
FAU - Fernandez-Ibarra, Cristina
AU  - Fernandez-Ibarra C
AD  - Department of Oncology, Novartis Pharma AG, Basel, Switzerland.
FAU - Lu, Hong
AU  - Lu H
AD  - Department of Oncology, Novartis Pharmaceuticals Corporation, East Hanover, New 
      Jersey, USA.
FAU - Pain, Scott
AU  - Pain S
AD  - Department of Oncology, Novartis Pharma AG, Basel, Switzerland.
FAU - Akimov, Mikhail
AU  - Akimov M
AD  - Department of Oncology, Novartis Pharma AG, Basel, Switzerland.
FAU - Iyer, Swaminathan Padmanabhan
AU  - Iyer SP
AD  - Department of Hematology, Houston Methodist Cancer Center, Houston, Texas, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT00708292
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20150324
PL  - United States
TA  - Cancer
JT  - Cancer
JID - 0374236
RN  - 0 
      (5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic 
      acid ethylamide)
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (Isoxazoles)
RN  - 0 (Resorcinols)
RN  - 69G8BD63PP (Bortezomib)
SB  - IM
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Bortezomib/administration & dosage
MH  - Female
MH  - HSP90 Heat-Shock Proteins/*antagonists & inhibitors
MH  - Humans
MH  - Isoxazoles/administration & dosage/*therapeutic use
MH  - Male
MH  - Multiple Myeloma/*drug therapy/metabolism/pathology
MH  - Resorcinols/administration & dosage/*therapeutic use
OTO - NOTNLM
OT  - AUY922
OT  - bortezomib
OT  - heat shock protein 90
OT  - heat shock protein 90 inhibitors
OT  - proteasome inhibitor
OT  - relapsed or refractory multiple myeloma
EDAT- 2015/03/27 06:00
MHDA- 2016/09/01 06:00
CRDT- 2015/03/27 06:00
PHST- 2014/12/29 00:00 [received]
PHST- 2015/01/20 00:00 [accepted]
PHST- 2015/03/27 06:00 [entrez]
PHST- 2015/03/27 06:00 [pubmed]
PHST- 2016/09/01 06:00 [medline]
AID - 10.1002/cncr.29339 [doi]
PST - ppublish
SO  - Cancer. 2015 Jul 1;121(13):2185-92. doi: 10.1002/cncr.29339. Epub 2015 Mar 24.