title: Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer.
abstract: OBJECTIVE
  This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor.
  
  
  METHODS
  Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125-16 mg/m2/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Pharmacokinetic (PK) evaluations were performed. Exploratory PK/pharmacodynamic analyses investigated the relationship between litronesib plasma exposure and changes in phosphohistone H3 (pHH3) levels.
  
  
  RESULTS
  One hundred and seventeen patients with advanced malignancies were enrolled. Neutropenia was the primary dose-limiting toxicity. Prophylactic pegfilgrastim reduced neutropenia frequency and severity, allowing administration of higher litronesib doses, but increases in the incidences of mucositis and stomatitis were observed. Among 86 response-evaluable patients, 2 patients (2%) achieved partial response, both on the Days 1, 2, 3 regimen (5 and 6 mg/m2/day with pegfilgrastim), and 17 patients (20%) maintained stable disease for ≥6 cycles. Dose-dependent increases in litronesib plasma exposure were observed, with minor intra- and inter-cycle accumulation, along with exposure-dependent increases in pHH3 expression in tumor and skin biopsies.
  
  
  CONCLUSIONS
  On the basis of the results of these studies, two regimens were selected for Phase 2 exploration: 6 mg/m2/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/m2/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle.
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA. jinfante@tnonc.com.|Tennessee Oncology PLLC, 250 25th Ave N. Suite 100, Nashville, TN, 37203, USA. jinfante@tnonc.com.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: South Texas Accelerated Research Therapeutics, LLC, San Antonio, TX, USA.
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: University of New Mexico, Albuquerque, NM, USA.|University of Vermont Cancer Center, Burlington, VT, USA.
authors.forename: Claire F
authors.initials: CF
authors.lastname: Verschraegen
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Olszanski
authors.affiliation: University of New Mexico, Albuquerque, NM, USA.
authors.forename: Montaser
authors.initials: M
authors.lastname: Shaheen
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA.|Tennessee Oncology PLLC, 250 25th Ave N. Suite 100, Nashville, TN, 37203, USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.affiliation: South Texas Accelerated Research Therapeutics, LLC, San Antonio, TX, USA.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.affiliation: South Texas Accelerated Research Therapeutics, LLC, San Antonio, TX, USA.
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.affiliation: South Texas Accelerated Research Therapeutics, LLC, San Antonio, TX, USA.
authors.forename: Muralidhar
authors.initials: M
authors.lastname: Beeram
authors.affiliation: Eli Lilly and Co., Indianapolis, IN, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Hynes
authors.affiliation: Eli Lilly and Co., Indianapolis, IN, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Leohr
authors.affiliation: Eli Lilly and Co., Indianapolis, IN, USA.
authors.forename: Aimee Bence
authors.initials: AB
authors.lastname: Lin
authors.affiliation: Eli Lilly and Co., Indianapolis, IN, USA.
authors.forename: Lily Q
authors.initials: LQ
authors.lastname: Li
authors.affiliation: Eli Lilly and Co., Indianapolis, IN, USA.|Berry Consultants, Austin, TX, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: McGlothlin
authors.affiliation: Eli Lilly and Co., Indianapolis, IN, USA.
authors.forename: Daphne L
authors.initials: DL
authors.lastname: Farrington
authors.affiliation: Eli Lilly and Co., Indianapolis, IN, USA.|Takeda Oncology, Cambridge, MA, USA.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Westin
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.|University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004334:Drug Administration Schedule; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols; D011994:Recombinant Proteins / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013830:Thiadiazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: C470243:KIF11 protein, human; D011994:Recombinant Proteins; D013449:Sulfonamides; D013830:Thiadiazoles; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; C000591843:litronesib; D016547:Kinesins; D000069585:Filgrastim
keywords: Antimitotic; Eg5; KSP inhibitor; Kinesin spindle protein (KSP); Phase 1