Phase 1 Study of ABT‐751 in Combination With CAPIRI (Capecitabine and Irinotecan) and Bevacizumab in Patients With Advanced Colorectal Cancer
Autor: | Antonio Jimeno, Ross C. Donehower, Runyan Jin, Ping He, Wells A. Messersmith, Gretchen E. Taylor, W. Thomas Purcell, Arvind Dasari, Rosalind Walker, Daniel A. Laheru, Manuel Hidalgo, Michelle A. Rudek |
---|---|
Rok vydání: | 2016 |
Předmět: |
Adult
Male 0301 basic medicine medicine.medical_specialty Bevacizumab Colorectal cancer colorectal cancer Therapeutics Pharmacology Deoxycytidine Gastroenterology Capecitabine 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans Pharmacology (medical) tubulin inhibitor Aged Aged 80 and over Sulfonamides business.industry toxicity Middle Aged medicine.disease 3. Good health Irinotecan Regimen 030104 developmental biology 030220 oncology & carcinogenesis Toxicity Camptothecin Drug Therapy Combination Female Fluorouracil Colorectal Neoplasms business pharmacokinetics Febrile neutropenia Follow-Up Studies medicine.drug |
Zdroj: | Journal of Clinical Pharmacology |
ISSN: | 1552-4604 0091-2700 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |