Metronomic chemotherapy and celecoxib
Subtitle: an antiangiogenic approach for pediatric cancer.
Published: 2005
Language: eng
Number of pages: 273
Description: Celecoxib and low dose metronomic (frequently administered) vinblastine or cyclophosphamide were studied as an antiangiogenic therapy for pediatric cancer patients. This Phase I study was the first investigation of this drug combination in children and in the general population. We studied 33 children and demonstrated short-term safety of this regimen (median duration 8.5 weeks (range 3-62.5 weeks)). Tolerable long-term administration to four patients for 7, 7.5, 15 and 18 months was also encouraging.In an attempt to assess the activity of this treatment, we evaluated bFGF, VEGF, sVCAM-1, slCAM-1, TSP-1 and endostatin as surrogate markers of angiogenesis. Variation in the monthly concentrations of these markers did not correlate with progressive or stable disease. While there were no objective responses, four patients had extended periods of stable disease which is encouraging in Phase I setting.Pediatric pharmacokinetic studies of low dose chemotherapy have not been reported. After improving on available analytical methodology, we described the disposition of low dose vinblastine and cyclophosphamide in children. Vinblastine pharmacokinetics appear not to have age-related effects while cyclophosphamide pharmacokinetics do. These pharmacokinetic studies demonstrated that antiangiogenic concentrations of the agents studied had been reached.We gained valuable and novel information regarding the pharmacokinetics of these drugs in children. In particular, the disposition of celecoxib in a pediatric population is of clinical significance as COX-2 inhibitors are an important sub-class of NSAIDs in the treatment of various conditions which are not adult-specific. We found that children cleared the drug approximately twice as fast and had a half-life that was half as long resulting in a significantly lower systemic exposure. Additionally, this was the first study to examine food co-administration on the pharmacokinetics of celecoxib in children. Absorption was significantly increased (60% (single dose) and 75% (steady state) increase in AUC) thereby aiding in achieving target antiangiogenic concentrations (500mug/L). This was also the first time that CYP2C9 genetic variation was correlated to celecoxib pharmacokinetic variation in children.Our findings support further investigation of antiangiogenic therapies as our treatment combination was well tolerated and may provide a novel means to prolong the progression-free interval and overall survival.
Notes: Source: Dissertation Abstracts International, Volume: 66-10, Section: B, page: 5339.

Thesis (Ph.D.)--University of Toronto, 2005.

Electronic version licensed for access by U. of T. users.