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

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/m2.

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/m2. 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.

Keywords: GRP78; IT-139; drug resistance; phase 1; ruthenium small molecule.

Figures

Figure 1

Mean plasma concentration-time profiles of ruthenium by dose on days 1, 8 and 28. Total ruthenium levels in plasma measured by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS) during cycle 1 day 1 (C1D1), prefusion on cycle 1 day 8 (C1D8) and cycle 2 day 1 (C2D1).

Figure 2

Plot with best overall response and study duration. Start time denotes the first dose of IT-139. Stop time denotes death or last follow-up if patient is still alive. Length of bars denotes study duration in weeks. Colour of bars shows best overall response. Diamonds mark the first instance of best overall response. *Hashed bar represents the time the patient was treated on a compassionate use extension study after completion of NCT01415297.

Figure 3

Change in target lesions from baseline stratified by cancer type.