me-344 and Neoplasms

The current phase 1, open-label, dose escalation study was conducted to establish the safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity of the novel mitochondrial inhibitor ME-344 in patients with refractory solid tumors.. Patients with refractory solid tumors were treated in a 3 + 3 dose escalation design. ME-344 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle and weekly thereafter. Pharmacokinetics was assessed on days 1 and 15 of the first cycle.. A total of 30 patients (median age, 65 years; 67% of whom were female) received ME-344. There were 5 dose-limiting toxicities reported. Four patients developed grade 3 neuropathy (2 patients each at doses of 15 mg/kg and 20 mg/kg) and 1 patient treated at a dose of 10 mg/kg developed a grade 3 acute myocardial infarction (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). The maximum tolerated dose (MTD) was defined as 10 mg/kg weekly. The most common adverse events were nausea, dizziness, and fatigue. At the MTD of 10 mg/kg, the maximal plasma concentration (Cmax) was 25.8 µg/mL and the area under the concentration curve from time zero to infinity was 25.9 hour*µg/mL. One patient with small cell lung cancer achieved a partial response for ≥ 52 weeks. Four patients had prolonged stable disease (1 patient each with urothelial carcinoma [47 weeks], carcinoid tumor [≥ 40 weeks], cervical leiomyosarcoma [39 weeks], and cervical cancer [≥ 31 weeks]).. The once-weekly administration of ME-344 was generally well tolerated in the current study, a first-in-human study; dose-limiting neuropathy was noted, but not at the MTD. Exposures at the 10-mg/kg dose level suggest a sufficient therapeutic index. The preliminary clinical activity as a monotherapy supports the further clinical development of ME-344 in combination with chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Isoflavones; Male; Maximum Tolerated Dose; Middle Aged; Mitochondria; Neoplasm Staging; Neoplasms; Prognosis; Safety; Tissue Distribution; Young Adult

Isoflavones isolated from members of the Fabaceae (primarily Leguminosae) family have been characterized for their phytoestrogenic properties, but certain derivatives have also shown potential as possible cancer therapeutic agents. ME-344, related to phenoxodiol (Fig. 1), is a second generation isoflavone with a recent history of both preclinical and early clinical testing. The drug has unusual cytotoxicity profiles, where cancer cell lines can be categorized as either intrinsically sensitive or resistant to the drug. Evolving studies show that the cytotoxic properties of the drug are enacted through targeting mitochondrial bioenergetics. While the drug has undergone early Phase I/II trials in solid tumors with confined dose limiting effects and some evidence of disease response, there is a continuing need to define specific cellular targets that determine sensitivity, with the long-term goal of applying such information to individualized therapy. This review article details some of the existing and ongoing studies that are assisting in the continued drug development processes that may lead to new drug application (NDA) status.

Topics: Antineoplastic Agents; Apoptosis; Clinical Trials, Phase I as Topic; Drug Screening Assays, Antitumor; Humans; Isoflavones; Neoplasms