title: A phase I, open-label, single-arm, dose-escalation study of E7107, a precursor messenger ribonucleic acid (pre-mRNA) splicesome inhibitor administered intravenously on days 1 and 8 every 21 days to patients with solid tumors.
abstract: The aim of this study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of E7107 in patients with advanced solid tumors. Patients in this phase I, open-label, single-arm, dose-escalation study had metastatic or locally advanced solid tumors and received E7107 as a 30-minute intravenous infusion at doses of 0.6, 1.2, 1.8, 2.4, 3.2, 4.3, and 5.7 mg/m(2). Twenty-six patients were enrolled in the study. At 5.7 mg/m(2), two patients experienced dose-limiting toxicities including diarrhea, vomiting, dehydration, and myocardial infarction on Days 1-3 following E7107 administration. Three additional patients were recruited at the lower dose and all six patients tolerated E7107 4.3 mg/m(2) with no dose-limiting toxicities. The maximum tolerated dose of E7107 was therefore 4.3 mg/m(2). The most common drug-related adverse events were nausea, vomiting, and diarrhea. Vision loss was experienced by two patients at Cycles 2 and 7, each patient receiving 3.2 mg/m(2) and 4.3 mg/m(2), respectively. This resulted in the study being put on clinical hold. Pharmacokinetic analysis showed that E7107 was rapidly distributed with a moderate elimination half-life (6-13 h) and high clearance. Exposure to E7107 was dose-related. The best tumor response was stable disease in eight patients. E7107 is a unique first-in-class molecule. The incidence of two cases of vision loss probably related to E7107 led to study discontinuation.
authors.affiliation: University of Texas M.D. Anderson Cancer Center, Unit 455, PO Box 301402, Houston, TX, 77030, USA, dshong@mdanderson.org.
authors.forename: D S
authors.initials: DS
authors.lastname: Hong
authors.forename: R
authors.initials: R
authors.lastname: Kurzrock
authors.forename: A
authors.initials: A
authors.lastname: Naing
authors.forename: J J
authors.initials: JJ
authors.lastname: Wheler
authors.forename: G S
authors.initials: GS
authors.lastname: Falchook
authors.forename: J S
authors.initials: JS
authors.lastname: Schiffman
authors.forename: N
authors.initials: N
authors.lastname: Faulkner
authors.forename: M J
authors.initials: MJ
authors.lastname: Pilat
authors.forename: J
authors.initials: J
authors.lastname: O'Brien
authors.forename: P
authors.initials: P
authors.lastname: LoRusso
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D003967:Diarrhea / Q000139:chemically induced; D004852:Epoxy Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D018942:Macrolides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012326:RNA Splicing / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D017381:Spliceosomes; D014786:Vision Disorders / Q000139:chemically induced; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; C557411:E 7107; D004852:Epoxy Compounds; D018942:Macrolides; D012333:RNA, Messenger