Safety Study of a New Schedule of Capecitabine and Docetaxel to Treat Cancers
The combination of capecitabine and docetaxel is given to treat several different types of cancer. Capecitabine is usually given by mouth for 14 days, and docetaxel is given IV on the first day of capecitabine. The effects of changes in the schedule of the combination of docetaxel and capecitabine has been examined in human breast cancer cells. A capecitabine by-product was given orally to breast cancer-bearing animals for 14 consecutive days. Docetaxel was given IV at a variety of times between days 1 and 15. The greatest reductions in the volume of the cancer were seen when animals were treated with docetaxel between days 6 and 10. In two other breast cancer models, the maximal degree of delay in growth of the tumors was achieved when the animals were treated with docetaxel on day 8 of a 14 day course of capecitabine. The extent of tumor response was not explained by changes in tumor levels of the enzyme thymidine phosphorylase, which is thought to be the mechanism behind the interaction of capecitabine and docetaxel. In the breast cancer cells, capecitabine increases the level of proteins which promote death of cancer cells, and it inhibits the levels of proteins which block death of cancer cells.
Our hypothesis is that capecitabine and docetaxel interact with each other, because capecitabine primes the pro-death machinery of the cell by increasing the ratio of death-promoting proteins to death-inhibiting proteins. Cells are more susceptible to killing by docetaxel when the pro-death machinery is activated by capecitabine.
This is a safety study to find the highest dose of capecitabine that can be given safely for 14 days, in combination with docetaxel given at a fixed dose on day 8. Once this dose of capecitabine has been determined, an additional nine patients with tumors that can be biopsied will be treated at this dose, and levels of capecitabine, its byproducts, and docetaxel will be measured in the bloodstream. Biopsies of tumors will also be taken before and after the docetaxel is given, and the levels of pro-death and anti-death proteins will be measured.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Study of a Novel Schedule of Capecitabine and Docetaxel in Patients With Advanced Solid Tumors|
- To determine the maximum tolerated dose, and dose limiting toxicity of capecitabine when given daily for 14 days with docetaxel given on day 8 of a 21 day cycle [ Time Frame: 3 weeks ] [ Designated as safety issue: Yes ]
- To determine the pharmacokinetic profile of capecitabine, 5-fluorouracil, and 5'-deoxy-5-fluorouridine following administration of docetaxel on day 8. [ Time Frame: 9 days ] [ Designated as safety issue: No ]
- To determine the expression of Bax, Bcl-2, and phosphorylated Bcl-2 at baseline and again on days 8 and 9 of capecitabine when given at the MTD [ Time Frame: 9 days ] [ Designated as safety issue: No ]
- To define pharmacodynamic relationships between observed changes in dihydropyrimidine dehydrogenase (DPD) and altered expression of Bax and Bcl-2 with clinical toxicities and antitumor response [ Time Frame: 9 days ] [ Designated as safety issue: Yes ]
|Study Start Date:||January 2003|
|Study Completion Date:||March 2006|
|Primary Completion Date:||September 2005 (Final data collection date for primary outcome measure)|
Experimental: Capecitabine and Docetaxel
Escalating doses of capecitabine days 1-14 with a fixed dose of docetaxel on Day 8 of a 21 day cycle
Capecitabine at the following dose levels for 14 days every 21 days, beginning with dose level 1
Dose level -2 600 mg/m2 po BID
Dose level -1 700 mg/m2 po BID
Dose level 1 825 mg/m2 po BID
Dose level 2 1000 mg/m2 po BID
Other Name: XelodaDrug: Docetaxel
75 mg/m2 over one hour on day 8 of each cycle
Other Name: Taxotere
This is a phase I study using an accelerated titration design to determine the maximum tolerated dose (MTD) of capecitabine given orally on a BID schedule from days 1-14, in combination with docetaxel given at a fixed dose of 75 mg/m2 IV on day 8. Once the MTD of capecitabine has been determined, an additional nine patients with accessible tumors will be treated at the MTD. Pharmacokinetics of plasma capecitabine, 5-FU, 5'-deoxy-5-fluorouridine, and docetaxel will be assayed in these nine patients, and tumor biopsies will be taken to assess Bax:Bcl-2 ratios and Bcl-2 phosphorylation at several time points. The primary aim of this study will be to determine the maximum tolerated dose and dose limiting toxicities of capecitabine when given with a fixed dose of docetaxel on day 8 of a 21 day schedule. Secondary aims will include assessment of the pharmacokinetics of capecitabine and docetaxel on this schedule, and determination of intratumoral Bax:Bcl-2, Bcl-2 phosphorylation, and DPD expression, and correlation with clinical toxicities and antitumor response.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00169000
|United States, New Hampshire|
|Norris Cotton Cancer Center|
|Lebanon, New Hampshire, United States, 03756|
|Study Chair:||Gary N Schwartz, MD||Norris Cotton Cancer Center|