%0 Journal Article
%T 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.
%A Burris HA
%A Bakewell S
%A Bendell JC
%A Infante J
%A Jones SF
%A Spigel DR
%A Weiss GJ
%A Ramanathan RK
%A Ogden A
%A Von Hoff D
%J ESMO Open
%V 1
%N 6
%D 2016
%M 28848672
%F 6.883
%R 10.1136/esmoopen-2016-000154
%X <B>OBJECTIVE: </B>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.<BR><B>METHODS: </B>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/m2.<BR><B>RESULTS: </B>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/m2. IT-139 exhibited first-order linear pharmacokinetics.<BR><B>CONCLUSIONS: </B>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.<BR><B>BACKGROUND: </B>NCT01415297.