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

Howard A. Burris, Suzanne Bakewell, Johanna C. Bendell, Jeffrey Infante, Suzanne F. Jones, David R. Spigel, Glen J. Weiss, Ramesh K. Ramanathan, Angela Ogden, Daniel Von Hoff

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere000154
JournalESMO Open
Volume1
Issue number6
DOIs
StatePublished - Dec 2016

Keywords

  • GRP78
  • IT-139
  • drug resistance
  • phase 1
  • ruthenium small molecule

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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