Phase 1, open‐label, dose escalation, safety, and pharmacokinetics study of ME‐344 as a single agent in patients with refractory solid tumors. Issue 7 (19th November 2014)

• Record Type: Journal Article
• Authors: Bendell, Johanna C.; Patel, Manish R.; Infante, Jeffrey R.; Kurkjian, Carla D.; Jones, Suzanne F.; Pant, Shubham; Burris, Howard A.; Moreno, Ofir; Esquibel, Vanessa; Levin, Wendy; Moore, Kathleen N.
• Is Part Of: Cancer. Volume 121:Issue 7(2015)
• Page Start: 1056
• Page End: 1063
• Publication Date: 2014-11-19
• Subjects: Cancer -- Periodicals; Cancer -- Cytopathology -- Periodicals; 616.99405
• DOI: 10.1002/cncr.29155
• Languages: English
• ISSNs: 0008-543X

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="cncr29155-sec-0001" sec-type="section"> <title>BACKGROUND</title> <p>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.</p> </sec> <sec id="cncr29155-sec-0002" sec-type="section"> <title>METHODS</title> <p>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.</p> </sec> <sec id="cncr29155-sec-0003" sec-type="section"> <title>RESULTS</title> <p>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 (C<sub>max</sub>) 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]).</p> </sec> <sec id="cncr29155-sec-0004" sec-type="section"> <title>CONCLUSIONS</title> <p>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. <bold><italic>Cancer 2015;121:1056–1063</italic>.</bold> © <italic>2014 American Cancer Society</italic>.</p> </sec> </abstract>