title: A pilot pharmacokinetic and antiangiogenic biomarker study of celecoxib and low-dose metronomic vinblastine or cyclophosphamide in pediatric recurrent solid tumors.
abstract: Tumor vasculature is a reasonable target for cancer therapy and lower more frequent doses of traditional chemotherapeutics [low-dose metronomic (LDM) chemotherapy] has been shown to have antiangiogenic efficacy. This study evaluated the safety and pharmacokinetics of celecoxib and LDM vinblastine or cyclophosphamide in children with recurrent, refractory solid tumors. We also investigated whether a subset of circulating plasma proteins are surrogate markers of angiogenic activity. Thirty-three children were enrolled in this pilot study and received celecoxib (250 mg/m(2) PO b.i.d.) and either vinblastine (1 mg/m(2) IV 3 x /wk) or cyclophosphamide (30 mg/m(2) PO daily) continually. Celecoxib alone and with LDM chemotherapy was well tolerated and plasma concentrations were consistent with those shown to have antiangiogenic activity. Four patients (13%) had durable stable disease (28 to 78 wk) although no complete or partial responses were observed. The surrogate markers measured (vascular endothelial growth factor, basic fibroblast growth factor, soluble vascular cell adhesion molecule, soluble intercellular cell adhesion molecule, endostatin, and thrombospondin-1) were highly variable and no statistically significant relationship between them and disease progression or maintenance of stable disease was observed. We concluded that this regimen is well tolerated hence supporting the use of this form of therapy in pediatric patients. However, future studies should include more homogenous patient populations and focus on validating surrogate markers to monitor treatment activity.
authors.affiliation: New Agents and Innovative Therapy Program, Division of Hematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Diana
authors.initials: D
authors.lastname: Stempak
authors.forename: Janet
authors.initials: J
authors.lastname: Gammon
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Halton
authors.forename: Albert
authors.initials: A
authors.lastname: Moghrabi
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
authors.forename: Sylvain
authors.initials: S
authors.lastname: Baruchel
mesh_terms: D000293:Adolescent; D020533:Angiogenesis Inhibitors; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D000068579:Celecoxib; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010865:Pilot Projects; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D014747:Vinblastine / Q000008:administration & dosage*
chemical_list: D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D011720:Pyrazoles; D013449:Sulfonamides; D014747:Vinblastine; D003520:Cyclophosphamide; D000068579:Celecoxib