Journal
ESMO OPEN
Volume 1, Issue 6, Pages -Publisher
ELSEVIER
DOI: 10.1136/esmoopen-2016-000154
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Funding
- Niiki Pharma
- Intezyne Technologies
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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 treatmentemergent 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.
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