Metastatic Breast Cancer Clinical Trial
Official title:
Phase I Study of a Novel Schedule of Capecitabine and Docetaxel in Patients With Advanced Solid Tumors
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.
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. ;
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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