A first-in-human dose-escalation study of ME-143, a second generation NADH oxidase inhibitor, in patients with advanced solid tumorsReport as inadecuate




A first-in-human dose-escalation study of ME-143, a second generation NADH oxidase inhibitor, in patients with advanced solid tumors - Download this document for free, or read online. Document in PDF available to download.

Investigational New Drugs

, Volume 32, Issue 1, pp 87–93

First Online: 24 March 2013Received: 09 January 2013Accepted: 07 March 2013DOI: 10.1007-s10637-013-9949-4

Cite this article as: Pant, S., Burris, H.A., Moore, K. et al. Invest New Drugs 2014 32: 87. doi:10.1007-s10637-013-9949-4 Summary

Background ME-143, a second-generation tumor-specific NADH oxidase inhibitor, is broadly active against human cancers in vitro and in vivo. This first-in-human dose-escalation study evaluated the dose-limiting toxicities DLTs, pharmacokinetics, safety, tolerability, and preliminary anti-tumor activity of ME-143 in patients with advanced solid tumors. Methods Patients with advanced solid tumors were treated in a 3 + 3 escalation design. ME-143 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle, and weekly thereafter; the final cohort received twice-weekly treatment. Samples for pharmacokinetic analysis were collected during cycle 1. Treatment continued until disease progression or unacceptable toxicity. Results Eighteen patients were treated: 2.5 mg-kg n = 3; 5 mg-kg n = 3; 10 mg-kg n = 3; 20 mg-kg n = 6; 20 mg-kg twice-weekly n = 3. There were no DLTs observed. Nearly all treatment-related toxicities were grade 1-2, specifically all grades nausea 22 % and fatigue 17 %. Two patients experienced infusion reactions at the 20 mg-kg dose level, one of which was grade 4. Stable disease was documented in three patients with colorectal cancer, cholangiocarcinoma, and anal cancer. Pharmacokinetic exposures were linear and dose-dependent, with a half-life of approximately 5 h. Conclusions ME-143 was well-tolerated when administered intravenously at the maximally administered-recommended phase 2 dose of 20 mg-kg once weekly to patients with advanced solid tumors. Though limited clinical activity was observed with monotherapy, inhibitors of tumor-specific NADH oxidase such as ME-143 may derive their greatest benefit in combination with cytotoxic chemotherapy.

KeywordsME-143 tNOX Dose escalation Isoflavone Apoptosis Previous presentations2012 American Society of Clinical Oncology Annual Meeting – Kurkjian et al, J Clin Oncol 30, 2012 suppl; abstr 3067

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Author: Shubham Pant - Howard A. BurrisIII - Kathleen Moore - Johanna C. Bendell - Carla Kurkjian - Suzanne F. Jones - Ofir More

Source: https://link.springer.com/







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