title: Evaluation of the oral antimitotic agent (ABT-751) in dogs with lymphoma.
abstract: BACKGROUND
  ABT-751 is a novel orally available antimitotic agent that targets microtubule polymerization. This mechanism may suggest potential activity in canine lymphoma.
  
  
  OBJECTIVE
  Determine a maximum tolerated dose for ABT-751, and assess long-term tolerability and activity in canine lymphoma.
  
  
  METHODS
  Thirty dogs with newly diagnosed (n = 19) or relapsed (n = 11) non-Hodgkin's lymphoma.
  
  
  METHODS
  Dogs (n = 11) were enrolled in a rapid dose escalation study to define the maximum tolerated dose. Upon definition of a maximally tolerated dose, a cohort expansion of 19 dogs allowed verification of long-term tolerability and assessment of activity. Study endpoints in the cohort expansion included chronic tolerability, response rate, response duration, and time to progression. Additional endpoints included serum pharmacokinetics, lymph node drug concentrations, and changes in circulating endothelial cells.
  
  
  RESULTS
  The maximum tolerated dose of ABT-751 was 350 mg/m(2) PO q24h. Dose-limiting toxicities included vomiting and diarrhea, which resolved with a schedule adjustment to 350 mg/m(2) PO q48h. ABT-751 was consistently detected in lymphoma tissue samples from dogs treated at or above the maximum tolerated dose. In the cohort expansion, objective responses were seen in 3/15 (20%) dogs with a response duration ranging from 21 to 111 days. Decreases in circulating endothelial cells were seen in 10 dogs at day 7 (2 responding dogs and 8 nonresponding dogs).
  
  
  CONCLUSIONS
  ABT-751 was well tolerated at 350 mg/m(2) PO q24h for 7 days and then q48h thereafter. Activity of ABT-751 suggested a rationale for additional studies of ABT-751 as part of a combination chemotherapy protocol for lymphoma or other canine cancers.
authors.affiliation: Animal Clinical Investigation, LLC and The Oncology Service, Washington, DC 20016, USA.
authors.forename: M
authors.initials: M
authors.lastname: Silver
authors.forename: A
authors.initials: A
authors.lastname: Rusk
authors.forename: B
authors.initials: B
authors.lastname: Phillips
authors.forename: E
authors.initials: E
authors.lastname: Beck
authors.forename: M
authors.initials: M
authors.lastname: Jankowski
authors.forename: J
authors.initials: J
authors.lastname: Philibert
authors.forename: K
authors.initials: K
authors.lastname: Hahn
authors.forename: E
authors.initials: E
authors.lastname: Hershey
authors.forename: E
authors.initials: E
authors.lastname: McKeegan
authors.forename: J
authors.initials: J
authors.lastname: Bauch
authors.forename: A
authors.initials: A
authors.lastname: Krivoshik
authors.forename: C
authors.initials: C
authors.lastname: Khanna
mesh_terms: D000284:Administration, Oral; D000818:Animals; D050256:Antimitotic Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood; D015331:Cohort Studies; D004283:Dog Diseases / Q000188:drug therapy* / Q000473:pathology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D008228:Lymphoma, Non-Hodgkin / Q000097:blood / Q000188:drug therapy / Q000473:pathology / Q000662:veterinary*; D008297:Male; D020714:Maximum Tolerated Dose; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood
chemical_list: C490492:ABT751; D050256:Antimitotic Agents; D013449:Sulfonamides