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

Abstract

SummaryBackground 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.

Phase 1, open‐label, dose escalation, safety, and pharmacokinetics study of ME‐344 as a single agent in patients with refractory solid tumors

“…ME‐344 has a mechanism of action that is distinct from ME‐143, a related drug candidate currently under clinical evaluation . The overall safety profile of ME‐344 was similar to that described in the first‐in‐human trial of ME‐143, with the exception of the AE of peripheral neuropathy observed in the current trial.…”

Novel flavonoids as anti-cancer agents: mechanisms of action and promise for their potential application in breast cancer

“…The accumulating knowledge on the mechanism of action of flavonoids, as briefly summarised here, together with information on different structure--activity relationships has led to promising new research rationales. In fact, there are several examples of promising novel flavonoids with improved properties that are currently at different stages of development towards their potential application in the treatment of ovarian and breast cancer [48][49][50].…”

Redox Signaling and Bioenergetics Influence Lung Cancer Cell Line Sensitivity to the Isoflavone ME-344

“…Mechanistically, proapoptotic effects may result from interference with mitochondrial functions (Kamsteeg et al, 2003) and interference with plasma membrane electron transport and/or cell surface thiol: disulfide exchange reactions (Morre and Morre, 2003;Herst et al, 2007). Downstream of such events, phenoxodiol derivatives can activate caspase-dependent and independent apoptotic pathways, perhaps through protein kinase B (Akt) signaling events (Wang et al, 2011;Pant et al, 2014). Related isoflavones alter mitochondrial membrane potential, deplete ATP, reduce steady-state levels of cytochrome c oxidase (complex IV of electron transport chain), and might eventually inhibit mammalian target of rapamycin (mTOR) activity .…”