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A first-in-human dose-escalation study of ME-143, a second generation NADH oxidase inhibitor, in patients with
Shubham Pant1, Howard A Burris, Kathleen Moore
1SCRI, University of Oklahoma, Oklahoma City, OK, USA.
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.
Insights
ME-143, a novel cancer drug, was well-tolerated in a Phase 1 trial for advanced solid tumors. While monotherapy showed limited activity, further research in combination therapy is warranted.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- ME-143 is a second-generation inhibitor targeting tumor-specific NADH oxidase.
- It has demonstrated broad anti-cancer activity in preclinical studies.
- This study represents the first-in-human evaluation of ME-143.
Purpose of the Study:
- To assess the dose-limiting toxicities (DLTs) of ME-143.
- To evaluate the safety, tolerability, and pharmacokinetics of ME-143.
- To explore the preliminary anti-tumor activity of ME-143 in patients with advanced solid tumors.
Main Methods:
- A 3+3 dose-escalation design was employed.
- ME-143 was administered intravenously to patients with advanced solid tumors.
- Pharmacokinetic samples were collected during the first cycle, and treatment continued until disease progression or toxicity.
Main Results:
- Eighteen patients received ME-143 at doses ranging from 2.5 to 20 mg/kg.
- No dose-limiting toxicities were observed; most toxicities were grade 1/2 (nausea, fatigue).
- One grade 4 infusion reaction occurred at 20 mg/kg; stable disease was noted in three patients.
Conclusions:
- ME-143 was well-tolerated at the recommended Phase 2 dose of 20 mg/kg weekly.
- Monotherapy showed limited clinical activity.
- Inhibitors of tumor-specific NADH oxidase, like ME-143, may be more effective in combination with chemotherapy.
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