A phase I study of axitinib (AG-013736) in combination with bevacizumab plus chemotherapy or chemotherapy alone in patients with metastatic colorectal cancer and other solid tumors.
BACKGROUND
Axitinib and bevacizumab are targeted therapies against the vascular endothelial growth factor pathway.


METHODS
Patients with previously treated solid tumors received axitinib (starting dose 5 mg twice daily) combined with FOLFOX plus bevacizumab (1, 2, or 5 mg/kg, cohorts 1-3, respectively), FOLFIRI (cohort 4), or FOLFOX (cohort 5). Safety and pharmacokinetics were assessed.


RESULTS
Thirty patients were enrolled (n = 16, 8, and 6 for cohorts 1-3, 4, and 5, respectively). Plasma concentrations and pharmacokinetic (PK) parameters were similar when drugs were administered alone and in various combinations. Most treatment-emergent adverse events (AEs) were mild to moderate and clinically manageable (most common: nausea, fatigue, diarrhea, anorexia, hypertension). Two of the four patients receiving axitinib with FOLFOX plus 5 mg/kg bevacizumab experienced dose-limiting toxicity (DLT) of inability to resume treatment for 14 days following treatment interruption (associated AE: hypertension); the maximum tolerated dose of bevacizumab in this combination was 2 mg/kg. No DLTs occurred with axitinib plus FOLFIRI or FOLFOX. Ten patients had RECIST-confirmed partial tumor responses (objective response rate: 33.3%).


CONCLUSIONS
Axitinib is well tolerated in combination with FOLFOX, FOLFIRI, or FOLFOX plus 2 mg/kg bevacizumab. PK interactions appear to be absent.
Sharma
S
S
Section of Gastrointestinal Oncology, Nevada Cancer Institute, Las Vegas, NV. Electronic address: sunil.sharma@hci.utah.edu.
Abhyankar
V
V
Department of Internal Medicine, Eastern Carolina Internal Medicine, Pollocksville, NC.
Burgess
R E
RE
Department of Internal Medicine, Eastern Carolina Internal Medicine, Pollocksville, NC.
Infante
J
J
Drug Development and Gastrointestinal Cancer Research, Sarah Cannon Research Institute, Nashville, TN.
Trowbridge
R C
RC
Indiana Oncology Hematology Consultants, St Francis Cancer Care Center, Indianapolis, IN.
Tarazi
J
J
Oncology Development, Pfizer, San Diego, CA.
Kim
S
S
Oncology Development, Pfizer, San Diego, CA.
Tortorici
M
M
Oncology Development, Pfizer, San Diego, CA.
Chen
Y
Y
Oncology Development, Pfizer, San Diego, CA.
Robles
R L
RL
Bay Area Cancer Research Group, Department of Medical Oncology and Hematology, Concord, CA, USA.
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D000077784:Axitinib; D000068258:Bevacizumab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D007191:Indazoles / Q000008:administration & dosage* / Q000009:adverse effects; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007093:Imidazoles; D007191:Indazoles; D009944:Organoplatinum Compounds; D000068258:Bevacizumab; D000077784:Axitinib; D002955:Leucovorin; D005472:Fluorouracil