Phase 1, Open-Label, Dose Escalation, Safety, and Pharmacokinetics Study of ME-344 as a Single Agent in Patients With Refractory Solid Tumors

BACKGROUND: The current phase 1, open-label, dose escalation study was conducted to establish the safety, tolerability, pharmaco-kinetic profile, and preliminary antitumor activity of the novel mitochondrial inhibitor ME-344 in patients with refractory solid tumors. METHODS: Patients with refractory solid tumors were treated in a 313 dose escalation design. ME-344 was administered via intrave-nous 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. RESULTS: 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 mg/mL and the area under the concentration curve from time zero to infinity was 25.9 hour*mg/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]). CONCLUSIONS: 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-34