PMID- 28848672
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210212
IS  - 2059-7029 (Print)
IS  - 2059-7029 (Electronic)
IS  - 2059-7029 (Linking)
VI  - 1
IP  - 6
DP  - 2016
TI  - Safety and activity of IT-139, a ruthenium-based compound, in patients with 
      advanced solid tumours: a first-in-human, open-label, dose-escalation phase I 
      study with expansion cohort.
PG  - e000154
LID - S2059-7029(20)32506-0 [pii]
LID - 10.1136/esmoopen-2016-000154 [doi]
LID - e000154
AB  - OBJECTIVE: This phase I clinical study (NCT01415297) evaluated the safety, 
      tolerability, maximum-tolerated dose (MTD), pharmacokinetics and pharmacodynamics 
      of IT-139 (formerly NKP-1339) monotherapy in patients with advanced solid 
      tumours. IT-139, sodium trans-(tetrachlorobis(1H-indazole)ruthenate(III)), is a 
      novel small molecule that suppresses the stress induction of GRP78 in tumour 
      cells. GRP78 is a key regulator of misfolded protein processing, and its 
      upregulation in tumours is associated with intrinsic and drug-induced resistance. 
      METHODS: Forty-six patients with advanced solid tumours refractory to treatment 
      received intravenous infusions of IT-139 on days 1, 8 and 15 for every 28 days, 
      and doses were evaluated across nine cohorts at 20, 40, 80, 160, 320, 420, 500, 
      625 and 780 mg/m(2). RESULTS: Overall, IT-139 was well tolerated. The 
      treatment-emergent adverse events (AEs) occurring in >/=20% of patients were 
      nausea, fatigue, vomiting, anaemia and dehydration. The majority of patients had 
      AEs that were </=grade 2, regardless of relationship with the study drug. Of the 
      total 38 efficacy-evaluable patients, one patient with a carcinoid tumour 
      achieved a durable partial response. Nine additional patients achieved stable 
      disease . The MTD was determined to be 625 mg/m(2). IT-139 exhibited first-order 
      linear pharmacokinetics. CONCLUSIONS: IT-139 demonstrated a manageable safety 
      profile at the MTD and modest anti-tumour activity in this study of patients with 
      solid tumours refractory to treatment. The lack of dose-limiting haematological 
      toxicity and the absence of neurotoxicity position IT-139 well for use in 
      combination with a broad spectrum of anticancer drugs. TRIAL REGISTRATION NUMBER: 
      NCT01415297.
FAU - Burris, Howard A
AU  - Burris HA
AD  - Sarah Cannon Research Institute, Nashville, Tennessee, USA.
FAU - Bakewell, Suzanne
AU  - Bakewell S
AD  - Intezyne Technologies, Tampa, Florida, USA. Electronic address: 
      suzanne.bakewell@intezyne.com.
FAU - Bendell, Johanna C
AU  - Bendell JC
AD  - Sarah Cannon Research Institute, Nashville, Tennessee, USA.
FAU - Infante, Jeffrey
AU  - Infante J
AD  - Sarah Cannon Research Institute, Nashville, Tennessee, USA.
FAU - Jones, Suzanne F
AU  - Jones SF
AD  - Sarah Cannon Research Institute, Nashville, Tennessee, USA.
FAU - Spigel, David R
AU  - Spigel DR
AD  - Sarah Cannon Research Institute, Nashville, Tennessee, USA.
FAU - Weiss, Glen J
AU  - Weiss GJ
AD  - Cancer Treatment Centers of America, Western Regional Medical Center, Goodyear, 
      Arizona, USA.
FAU - Ramanathan, Ramesh K
AU  - Ramanathan RK
AD  - Translational Genomics Research Institute, Phoenix, Arizona, USA.
FAU - Ogden, Angela
AU  - Ogden A
AD  - Novateur Ventures,Vancouver, British Columbia, Canada.
FAU - Von Hoff, Daniel
AU  - Von Hoff D
AD  - Translational Genomics Research Institute, Phoenix, Arizona, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT01415297
PT  - Journal Article
DEP - 20170223
PL  - England
TA  - ESMO Open
JT  - ESMO open
JID - 101690685
CIN - ESMO Open. 2017 Aug 17;2(3):e000239. PMID: 29225925
PMC - PMC5548977
OTO - NOTNLM
OT  - GRP78
OT  - IT-139
OT  - drug resistance
OT  - phase 1
OT  - ruthenium small molecule
EDAT- 2017/08/30 06:00
MHDA- 2017/08/30 06:01
PMCR- 2017/02/23
CRDT- 2017/08/30 06:00
PHST- 2016/12/22 00:00 [received]
PHST- 2017/01/10 00:00 [revised]
PHST- 2017/01/11 00:00 [accepted]
PHST- 2017/08/30 06:00 [entrez]
PHST- 2017/08/30 06:00 [pubmed]
PHST- 2017/08/30 06:01 [medline]
PHST- 2017/02/23 00:00 [pmc-release]
AID - S2059-7029(20)32506-0 [pii]
AID - esmoopen-2016-000154 [pii]
AID - 10.1136/esmoopen-2016-000154 [doi]
PST - epublish
SO  - ESMO Open. 2017 Feb 23;1(6):e000154. doi: 10.1136/esmoopen-2016-000154. 
      eCollection 2016.