PMID- 28550039
OWN - NLM
STAT- MEDLINE
DCOM- 20170810
LR  - 20210202
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 130
IP  - 5
DP  - 2017 Aug 3
TI  - A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or 
      refractory AL amyloidosis.
PG  - 597-605
LID - 10.1182/blood-2017-03-771220 [doi]
AB  - This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy 
      of the oral proteasome inhibitor (PI) ixazomib in patients with 
      relapsed/refractory immunoglobulin light chain (AL) amyloidosis. Ixazomib was 
      administered to adult patients with relapsed/refractory AL amyloidosis after 1 or 
      more prior lines of therapy (including bortezomib) on days 1, 8, and 15 of 28-day 
      cycles, for up to 12 cycles. Patients with less than partial response after 3 
      cycles received oral dexamethasone (40 mg, days 1-4) from cycle 4. A 3+3 
      dose-escalation phase was followed by 2 expansion cohorts (PI-naive and 
      PI-exposed patients) at the maximum tolerated dose (MTD). Twenty-seven patients 
      were enrolled: 11 during dose escalation (6 at 4.0 mg and 5 at 5.5 mg) and 16 
      during dose expansion (4.0 mg). Three patients experienced dose-limiting 
      toxicities: 1 at 4.0 mg and 2 at 5.5 mg; the MTD was determined as 4.0 mg. Most 
      common adverse events (AEs) included nausea, skin and subcutaneous tissue 
      disorders (SSTD), diarrhea, and fatigue; grade 3 or higher AEs included dyspnea, 
      fatigue, and SSTD. Overall, the hematologic response rate was 52% in patients 
      treated at the MTD (n = 21). Organ responses were seen in 56% of patients (5 
      cardiac, 5 renal). Median hematologic progression-free survival was 14.8 months; 
      1-year progression-free and overall survival rates were 60% and 85%, respectively 
      (median follow-up, 16.9 months). Weekly oral ixazomib appears to be active in 
      patients with relapsed/refractory AL amyloidosis, with a generally manageable 
      safety profile. The study was registered at clinicaltrials.gov as #NCT01318902 A 
      phase 3 study is ongoing (#NCT01659658).
CI  - (c) 2017 by The American Society of Hematology.
FAU - Sanchorawala, Vaishali
AU  - Sanchorawala V
AD  - Amyloidosis Center, Boston University School of Medicine, Boston, MA.
FAU - Palladini, Giovanni
AU  - Palladini G
AD  - Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San 
      Matteo, Pavia, Italy.
AD  - Department of Molecular Medicine, University of Pavia, Pavia, Italy.
FAU - Kukreti, Vishal
AU  - Kukreti V
AD  - Princess Margaret Hospital, Toronto, ON, Canada.
FAU - Zonder, Jeffrey A
AU  - Zonder JA
AD  - Barbara Ann Karmanos Cancer Institute, Detroit, MI.
FAU - Cohen, Adam D
AU  - Cohen AD
AD  - Fox Chase Cancer Center, Philadelphia, PA.
FAU - Seldin, David C
AU  - Seldin DC
AD  - Amyloidosis Center, Boston University School of Medicine, Boston, MA.
FAU - Dispenzieri, Angela
AU  - Dispenzieri A
AD  - Mayo Clinic, Rochester, MN.
FAU - Jaccard, Arnaud
AU  - Jaccard A
AD  - Centre Hospitalier Universitaire, Limoges, France.
FAU - Schonland, Stefan O
AU  - Schonland SO
AD  - Medical Department V, Amyloidosis Center, University Hospital of Heidelberg, 
      Heidelberg, Germany.
FAU - Berg, Deborah
AU  - Berg D
AD  - Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda 
      Pharmaceutical Company Limited, Cambridge, MA.
FAU - Yang, Huyuan
AU  - Yang H
AD  - Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda 
      Pharmaceutical Company Limited, Cambridge, MA.
FAU - Gupta, Neeraj
AU  - Gupta N
AD  - Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda 
      Pharmaceutical Company Limited, Cambridge, MA.
FAU - Hui, Ai-Min
AU  - Hui AM
AD  - Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda 
      Pharmaceutical Company Limited, Cambridge, MA.
FAU - Comenzo, Raymond L
AU  - Comenzo RL
AD  - Tufts Medical Center, Boston, MA.
FAU - Merlini, Giampaolo
AU  - Merlini G
AD  - Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San 
      Matteo, Pavia, Italy.
AD  - Department of Molecular Medicine, University of Pavia, Pavia, Italy.
LA  - eng
SI  - ClinicalTrials.gov/NCT01318902
SI  - ClinicalTrials.gov/NCT01659658
SI  - ClinicalTrials.gov/NCT01318902
SI  - ClinicalTrials.gov/NCT01659658
GR  - P30 CA022453/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20170526
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Boron Compounds)
RN  - 0 (Proteasome Inhibitors)
RN  - 71050168A2 (ixazomib)
RN  - TE7660XO1C (Glycine)
SB  - IM
EIN - Blood. 2020 Mar 26;135(13):1071. PMID: 32219354
MH  - Administration, Oral
MH  - Aged
MH  - Amyloidosis/*drug therapy/*mortality
MH  - Boron Compounds/*administration & dosage/adverse effects
MH  - Disease-Free Survival
MH  - Female
MH  - Follow-Up Studies
MH  - Glycine/administration & dosage/adverse effects/*analogs & derivatives
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Proteasome Inhibitors/*administration & dosage/adverse effects
MH  - Survival Rate
PMC - PMC6911836
COIS- Conflict-of-interest disclosure: V.S. received research support from Celgene; 
      Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda 
      Pharmaceutical Company Limited; Onyx; and Prothena Biosciences, Inc. G.P. 
      received honoraria and travel grants from Prothena Biosciences, Inc.; travel 
      grants from Celgene; and advisory board for Janssen-Cilag. V.K. received 
      honoraria from Celgene, Lundbeck, and Amgen. J.A.Z. received research support 
      from Celgene and Millennium Pharmaceuticals Inc., a wholly owned subsidiary of 
      Takeda Pharmaceutical Company Limited; consultancy for Millennium Pharmaceuticals 
      Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and 
      BMS, Janssen, Amgen, Prothena Biosciences, Inc., and Seattle Genetics. A.D.C. 
      received honoraria and membership on the board of directors or advisory committee 
      for Celgene, BMS, and Onyx. A.D. received research funding from Celgene; 
      Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda 
      Pharmaceutical Company Limited; and Janssen Research & Development. A.J. received 
      research funding from Celgene; honoraria from Millennium Pharmaceuticals Inc., a 
      wholly owned subsidiary of Takeda Pharmaceutical Company Limited; Janssen; and 
      Celgene. S.O.S. received research funding from Celgene and Janssen and honoraria 
      from Janssen, Prothena Biosciences, Inc., GlaxoSmithKline, and Celgene. D.B., 
      H.Y., N.G., and A.-M.H. are employed by Millennium Pharmaceuticals Inc., a wholly 
      owned subsidiary of Takeda Pharmaceutical Company Limited. R.L.C. had a 
      consultancy and membership on board of directors or advisory committee for 
      Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda 
      Pharmaceutical Company Limited, and received research funding from Millennium 
      Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company 
      Limited. G.M. had a consultancy from Millennium Pharmaceuticals Inc., a wholly 
      owned subsidiary of Takeda Pharmaceutical Company Limited; Pfizer; Janssen; and 
      Prothena Biosciences, Inc.
EDAT- 2017/05/28 06:00
MHDA- 2017/08/11 06:00
PMCR- 2017/08/03
CRDT- 2017/05/28 06:00
PHST- 2017/03/03 00:00 [received]
PHST- 2017/05/18 00:00 [accepted]
PHST- 2017/05/28 06:00 [pubmed]
PHST- 2017/08/11 06:00 [medline]
PHST- 2017/05/28 06:00 [entrez]
PHST- 2017/08/03 00:00 [pmc-release]
AID - S0006-4971(20)33131-1 [pii]
AID - 2017/771220 [pii]
AID - 10.1182/blood-2017-03-771220 [doi]
PST - ppublish
SO  - Blood. 2017 Aug 3;130(5):597-605. doi: 10.1182/blood-2017-03-771220. Epub 2017 
      May 26.