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, Ramesk K Ramanathan, Angela Ogden, Daniel Von Hoff

Research output: Contribution to journalArticle

30 Citations (Scopus)

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 1 2016
Externally publishedYes

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Ruthenium Compounds
Safety
Maximum Tolerated Dose
Neoplasms
Pharmacokinetics
Carcinoid Tumor
Dehydration
Drug Resistance
Intravenous Infusions
Pharmaceutical Preparations
Nausea
Vomiting
Fatigue
Anemia
Up-Regulation
Therapeutics
Sodium

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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

In: ESMO Open, Vol. 1, No. 6, e000154, 01.12.2016.

Research output: Contribution to journalArticle

Burris, Howard A. ; Bakewell, Suzanne ; Bendell, Johanna C. ; Infante, Jeffrey ; Jones, Suzanne F. ; Spigel, David R. ; Weiss, Glen J. ; Ramanathan, Ramesk K ; Ogden, Angela ; Von Hoff, Daniel. / 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. In: ESMO Open. 2016 ; Vol. 1, No. 6.
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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.",
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T2 - A first-in-human, open-label, dose-escalation phase i study with expansion cohort

AU - Burris, Howard A.

AU - Bakewell, Suzanne

AU - Bendell, Johanna C.

AU - Infante, Jeffrey

AU - Jones, Suzanne F.

AU - Spigel, David R.

AU - Weiss, Glen J.

AU - Ramanathan, Ramesk K

AU - Ogden, Angela

AU - Von Hoff, Daniel

PY - 2016/12/1

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N2 - 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.

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.

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KW - phase 1

KW - ruthenium small molecule

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