Safety Study of a New Schedule of Capecitabine and Docetaxel to Treat Cancers - Full Text View

Sponsors and Collaborators:	Dartmouth-Hitchcock Medical Center Hoffmann-La Roche
Information provided by:	Dartmouth-Hitchcock Medical Center
ClinicalTrials.gov Identifier:	NCT00169000

Purpose

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.

Condition	Intervention	Phase
Metastatic Breast Cancer	Drug: Capecitabine (Xeloda) Drug: Docetaxel (Taxotere)	Phase I

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study
Official Title:	Phase I Study of a Novel Schedule of Capecitabine and Docetaxel in Patients With Advanced Solid Tumors

Resource links provided by NLM:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer

Drug Information available for: Docetaxel Capecitabine

U.S. FDA Resources

Further study details as provided by Dartmouth-Hitchcock Medical Center:

Primary Outcome Measures:

To determine the maximum tolerated dose, and dose limiting
toxicity of capecitabine given daily for 14 days with
docetaxel given on day 8.

Secondary Outcome Measures:

To determine the pharmacokinetic profile of
capecitabine, 5-fluorouracil, and 5’-deoxy-5-
fluorouridine following administration of docetaxel on
day 8.
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.
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.

Estimated Enrollment:	33
Study Start Date:	January 2003
Study Completion Date:	February 2007

Detailed Description:

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients with a histologically or cytologically proven metastatic solid tumor.
Patients with measurable disease or an evaluable bone lesion that will not undergo biopsy.
Patients treated within the additional cohort at MTD will have metastatic breast cancer with a site of disease that is amenable to percutaneous FNA and must be willing to undergo serial FNA biopsies of their primary tumor.
Age > 18 years.
Life expectancy of at least 6 months.
ECOG performance status 0-2.
Adequate hematologic, hepatic, and renal function
Patients must have an intact upper gastrointestinal tract, be able to swallow tablets, and not have a malabsorption syndrome.

Exclusion Criteria:

No significant uncontrolled infectious or cardiovascular disease, or a myocardial infarction within the prior 12 months.
No prior organ allograft.
No prior treatment with capecitabine or with docetaxel.
No prior unanticipated severe reaction to fluoropyrimidine therapy or known hypersensitivity to 5–fluorouracil.
No concurrent antacid therapy is allowed.
No other significant medical/surgical diseases.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00169000

Locations

United States, New Hampshire
Norris Cotton Cancer Center
Lebanon, New Hampshire, United States, 03756

Sponsors and Collaborators

Dartmouth-Hitchcock Medical Center

Hoffmann-La Roche

Investigators

Study Chair:

Gary N Schwartz, MD

Norris Cotton Cancer Center

More Information

Additional Information:

Norris Cotton Cancer Center Home Page This link exits the ClinicalTrials.gov site

No publications provided

Study ID Numbers:	D-0139
Study First Received:	September 9, 2005
Last Updated:	April 8, 2007
ClinicalTrials.gov Identifier:	NCT00169000 History of Changes
Health Authority:	United States: Institutional Review Board

Keywords provided by Dartmouth-Hitchcock Medical Center:

breast cancer
capecitabine
docetaxel

pharmacokinetic/pharmacodynamic
bcl-2
bax

Study placed in the following topic categories:

Antimetabolites
Docetaxel
Capecitabine

Skin Diseases
Breast Neoplasms
Breast Diseases

Additional relevant MeSH terms:

Antimetabolites
Capecitabine
Antimetabolites, Antineoplastic
Skin Diseases
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Breast Neoplasms

Pharmacologic Actions
Docetaxel
Neoplasms
Neoplasms by Site
Therapeutic Uses
Breast Diseases

ClinicalTrials.gov processed this record on July 02, 2009