title: Phase 1 Study of ABT-751 in Combination With CAPIRI (Capecitabine and Irinotecan) and Bevacizumab in Patients With Advanced Colorectal Cancer.
abstract: ABT-751 is an orally bioavailable sulfonamide with antimitotic properties. A nonrandomized phase 1 dose-escalation study of ABT-751 in combination with CAPIRI (capecitabine and irinotecan) and bevacizumab was conducted to define the maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics in patients with advanced colorectal cancer. Patients were treated with ABT-751 daily for 7 days (alone) and then began 21-day cycles of treatment with ABT-751 daily and capecitabine twice daily for 14 days plus irinotecan on day 1 intravenously. Bevacizumab was added as standard of care at 7.5 mg/kg on day 1 after the first 2 dose levels. Because of intolerance to the regimen, a reduced dose of ABT-751 was also explored with reduced-dose and full-dose CAPIRI with bevacizumab. ABT-751 and irinotecan pharmacokinetics, ABT-751 glucuronidation, and protein binding were explored. Twenty-four patients were treated over 5 dose levels. The maximum tolerated dose was ABT-751 125 mg combined with full-dose CAPIRI and bevacizumab 7.5 mg/kg on day 1. DLTs were hypokalemia, elevated liver tests, and febrile neutropenia. ABT-751 is metabolized by UGT1A8 and to a lesser extent UGT1A4 and UGT1A1. Irinotecan and APC exposure were increased, SN-38 exposure was similar, and SN-38 glucuronide exposure was decreased. Clinically relevant alterations in ABT-751 and irinotecan pharmacokinetics were not observed. Despite modest efficacy, the combination of ABT-751, CAPIRI, and bevacizumab will not be studied further in colorectal cancer.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.affiliation: University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: Arvind
authors.initials: A
authors.lastname: Dasari
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Laheru
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Runyan
authors.initials: R
authors.lastname: Jin
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Walker
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Gretchen E
authors.initials: GE
authors.lastname: Taylor
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.|University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Ross C
authors.initials: RC
authors.lastname: Donehower
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.|Centro Integral Oncologico Clara Campal, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.|University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.|University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: W Thomas
authors.initials: WT
authors.lastname: Purcell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000097:blood; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000097:blood; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D015179:Colorectal Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D013449:Sulfonamides / Q000008:administration & dosage* / Q000097:blood
chemical_list: C490492:ABT751; D013449:Sulfonamides; D003841:Deoxycytidine; D000068258:Bevacizumab; D005472:Fluorouracil; D002166:Camptothecin
keywords: colorectal cancer; pharmacokinetics; toxicity; tubulin inhibitor