title: Phase 1, open-label, dose escalation, safety, and pharmacokinetics study of ME-344 as a single agent in patients with refractory solid tumors.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  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 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]).
  
  
  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-344 in combination with chemotherapy.
authors.affiliation: Sarah Cannon Research Institute, Nashville, Tennessee; Tennessee Oncology PLLC, Nashville, Tennessee.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.forename: Manish R
authors.initials: MR
authors.lastname: Patel
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Carla D
authors.initials: CD
authors.lastname: Kurkjian
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.forename: Shubham
authors.initials: S
authors.lastname: Pant
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: Ofir
authors.initials: O
authors.lastname: Moreno
authors.forename: Vanessa
authors.initials: V
authors.lastname: Esquibel
authors.forename: Wendy
authors.initials: W
authors.lastname: Levin
authors.forename: Kathleen N
authors.initials: KN
authors.lastname: Moore
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D007529:Isoflavones / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects*; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D012449:Safety; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007529:Isoflavones; C000597890:ME-344
keywords: ME-344; first-in-human; maximum tolerated dose (MTD); mitochondrial inhibitor; phase 1; refractory solid tumors