A multicenter, randomized, open-label study to assess the steady-state pharmacokinetics of bevacizumab given with either XELOX or FOLFOX-4 in patients with metastatic colorectal cancer

• Published in: Cancer chemotherapy and pharmacology Vol. 68; no. 5; pp. 1199 - 1206
• Main Authors: Zhi, Jianguo, Chen, Eric, Major, Pierre, Burns, Ivon, Robinson, Bridget, McKendrick, Joe, Rittweger, Karen, Abt, Markus, Goldstein, David
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.11.2011; Springer; Springer Nature B.V
• Subjects: Adult; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab; Biological and medical sciences; Cancer Research; Capecitabine; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Female; Fluorouracil - administration & dosage; Fluorouracil - analogs & derivatives; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Leucovorin - administration & dosage; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Neoplasm Metastasis; Oncology; Organoplatinum Compounds - administration & dosage; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; XELOX; Pharmacokinetics; FOLFOX-4; Bevacizumab; Antineoplastic agent; Rectal disease; Capecitabine; Multicenter study; Colorectal cancer; Monoclonal antibody; Metastasis; Randomization; Oxaliplatin; Intestinal disease; Advanced stage; Antiangiogenic agent; Pyrimidine nucleoside; Platinum II Complexes; Human; Fluoropyrimidine derivatives; Patient; Malignant tumor; Prodrug; Steady state; Colonic disease; Alkylating agent; Vascular endothelium growth factor; Digestive diseases; Therapeutic protocol; Cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-011-1606-z

Purpose To compare the pharmacokinetics (PK) of bevacizumab (BV) at steady-state under two different dosing regimens, 7.5 mg/kg q3w and 5.0 mg/kg q2w, concomitantly with a combination of capecitabine and oxaliplatin (XELOX) and FOLFOX-4 (oxaliplatin in combination with infusional 5-FU/LV), respectively, in patients with metastatic colorectal cancer (mCRC). Methods Patients were randomized in a 1:1 ratio to either XELOX + BV or FOLFOX-4 + BV. Blood samples for steady-state PK of BV were collected on day 1 of cycle 5 (at the earliest) for XELOX + BV treatment and day 1 of cycle 7 (at the earliest) for FOLFOX-4 + BV treatment. Results A total of 64 patients were enrolled, of which 37 were eligible for PK analyses. The primary PK parameter of BV, AUC ss(per week) , was statistically similar between the two dosing regimens with the 90% confidence interval in the commonly used no-effect boundaries of 0.8 and 1.25. The V ss and CL did not differ between the two regimens; t ½ during the PK cycle was also similar for both arms at approximately 16 days. These results demonstrated no clinically relevant change in BV PK when co-administered with either XELOX or FOLFOX-4. BV in combination with XELOX and FOLFOX-4 was generally well tolerated with no unexpected safety signals and no deaths. Nine patients in the XELOX + BV arm and 15 patients in the FOLFOX-4 + BV arm experienced at least one SAE (most commonly gastrointestinal disorders) which led to dose modification in 7 and 2 patients, respectively, and to premature withdrawal in 9 and 5 patients, respectively. All 64 patients experienced at least one non-serious AE. Laboratory tests and vital signs were unremarkable. Conclusions No clinically relevant differences in overall steady-state exposure of BV occurred when BV was given 7.5 mg/kg q3w in combination with XELOX or 5.0 mg/kg q2w with FOLFOX-4 in patients with mCRC, and the pharmacokinetics of BV were very similar between the two regimens. No unexpected adverse events or deaths were identified.