Abstract A17: ME-344, a novel mitochondrial oxygenase inhibitor: Results from a first-in-human Phase I study. (2013)

Abstract Background: ME-344 is a second generation isoflavone-derived drug candidate that causes caspase-independent cell death in multiple human tumor cell lines including CD44+/MyD88+ ovarian cancer stem cells by interfering with mitochondrial energy generation. Treatment with ME-344 results in decreased ATP production, an increase in reactive oxygen species and disruption of tumor cell mitochondrial integrity. Decreased ATP also lead to inhibition of mTOR1 and mTOR2-dependent signaling pathways via the activation of AMP kinase and the appearance of autophagic vacuoles. We report clinical and pharmacokinetic (PK) results from the first-in-human phase I study of ME-344. Methods: A 3+3 dose escalation design enrolled patients with refractory solid tumors in 6 cohorts at 1.25, 2.5, 5, 10, 15, and 20mg/kg IV weekly times 3, followed by 1 week of rest, then continuous weekly dosing. Restaging occurred every 2 cycles and PK was assessed at day 1 and 15 of cycle 1. Results: Safety: Thirty patients were enrolled. The MTD was established at 10 mg/kg. DLT's were observed at 15 mg/kg (2) and 20 mg/kg (2), all grade 3 neuropathy, and one patient at 10 mg/kg with cardiac chest pain. Possibly related grade 1/2 AE's occurring in &amp;gt;1 patient included: dizziness (5), fatigue (5), nausea (5), asthenia (3), diarrhea (3), dyspnea (3), vomiting (3), abdominal pain (2), chest pain (2), dysphonia (2), headache (2), and neuropathy (2). Pharmacokinetics: ME[[Unable to Display Character: &amp;#8208;]]344 plasma concentrations declined in a multi[[Unable to Display Character: &amp;#8208;]]exponential fashion, with a mean half-life of 6 hrs. There was a linear relationship between both Cmax and AUC as a function of dose (mg/kg), with no evidence of accumulation between Day 1 and Day 15. At the MTD of 10 mg/kg, Cmax was 25.78μg/mL and AUC∞ was 25.9 hr*μg/mL. Volume of distribution, half-life and clearance parameters appear dose[[Unable to Display Character: &amp;#8208;]]independent. Efficacy: Median time on treatment is 56 days (range 1 to 372+). To date, 1 confirmed PR (SCLC, duration 52+ weeks) and 7 prolonged SD (carcinoid (1), cervical (1), leiomyosarcoma (2), NSCLC (1), urothelial (1), uterine (1), 8 - 40+ weeks) have been observed in 23 patients evaluable for efficacy. Conclusions: ME-344 demonstrated dose-limiting toxicity of neuropathy, a known effect of mitochondrial respiratory chain inhibitors. PK data at the 10 mg/kg MTD dose level suggests a sufficient therapeutic index. Evidence of clinical activity at the MTD was observed and supports continued clinical development. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A17. Citation Format: Johanna C. Bendell, Manish Patel, Jeffrey R. Infante, Carla Kurkjian, Suzanne Jones, Shubham Pant, Howard A. Burris, John D. Hainsworth, Ofir Moreno, Kathleen Moore. ME-344, a novel mitochondrial oxygenase inhibitor: Results from a first-in-human Phase I study. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A17.