title: Phase Ib study of the mitochondrial inhibitor ME-344 plus topotecan in patients with previously treated, locally advanced or metastatic small cell lung, ovarian and cervical cancers.
abstract: Background This multicenter, open-label, phase Ib study was designed to assess the safety, pharmacokinetics and preliminary efficacy of ME-344, a mitochondrial inhibitor, administered in combination with the topoisomerase I inhibitor, topotecan, in patients with previously treated, locally advanced or metastatic small cell lung (SCLC), ovarian and cervical cancers. Patients and methods In Part 1, patients received ME-344 10 mg/kg intravenously weekly on days 1, 8, 15 and 22 in combination with topotecan 4 mg/m2on days 1, 8, and 15 of a 28 day cycle. Cycles were repeated until disease progression or unacceptable toxicity. Patients were evaluated for dose-limiting toxicity (DLT) in cycle 1 and ME-344 pharmacokinetic samples were obtained. In Part 2, patients with locally advanced or metastatic SCLC and ovarian cancer were enrolled in expansion cohorts treated at the recommended phase II dose (RP2D) determined in Part 1. Results Fourteen patients were enrolled in Part 1 and no DLTs were observed. The RP2D of ME-344 in combination with topotecan was established as 10 mg/kg. In Part 2, 32 patients were enrolled. The most common treatment-emergent all-grade and grade 3/4 toxicities included fatigue (65.2%, 6.5%), neutropenia (56.5%, 43.5%) and thrombocytopenia (50%, 23.9%). One patient with recurrent ovarian cancer experienced a partial response by RECIST 1.1 and 21 patients achieved stable disease as best response. Conclusions The combination of ME-344 10 mg/kg weekly and topotecan 4 mg/m2was tolerable, however, the degree of anti-cancer activity does not support further investigation of the combination in unselected patients with SCLC, ovarian and cervical cancers.
authors.affiliation: University of Colorado Cancer Center, 12801 E. 17th Avenue, Mailstop 8117, Aurora, CO, 80045, USA. Jennifer.diamond@ucdenver.edu.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Diamond
authors.affiliation: University of Washington/Seattle Cancer Care Alliance, Seattle, WA, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Goff
authors.affiliation: Sarah Cannon Research Institute UK, London, UK.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Forster
authors.affiliation: Sara Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.affiliation: Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: Britten
authors.affiliation: Pinnacle Oncology Hematology, Scottsdale, AZ, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gordon
authors.affiliation: Imperial College London, London, UK.
authors.forename: Hani
authors.initials: H
authors.lastname: Gabra
authors.affiliation: Oncology Hematology Care, Cincinnati, OH, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Waterhouse
authors.affiliation: MEI Pharma, San Diego, CA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Poole
authors.affiliation: University of Colorado Cancer Center, 12801 E. 17th Avenue, Mailstop 8117, Aurora, CO, 80045, USA.
authors.forename: D
authors.initials: D
authors.lastname: Ross Camidge
authors.affiliation: Sara Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Hamilton
authors.affiliation: Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Moore
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007529:Isoflavones / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage; D019772:Topotecan / Q000008:administration & dosage; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy*
chemical_list: D007529:Isoflavones; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; C000597890:ME-344
keywords: ME-344; Mitochondrial inhibitor; Ovarian cancer; Small cell lung cancer; Topotecan