Safety Study of a New Schedule of Capecitabine and Docetaxel to Treat Cancers

Metastatic Breast Cancer Clinical Trial

Official title:

Phase I Study of a Novel Schedule of Capecitabine and Docetaxel in Patients With Advanced Solid Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00169000
• Other study ID #: D-0139
• Status: Completed
• Phase: Phase 1
• First received: September 9, 2005
• Last updated: August 4, 2009
• Start date: January 2003
• Est. completion date: March 2006

Study information

• Verified date: August 2009
• Source: Dartmouth-Hitchcock Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: March 2006
• Est. primary completion date: September 2005
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Metastatic Breast Cancer

Intervention

Drug:
• Capecitabine
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
• Docetaxel
75 mg/m2 over one hour on day 8 of each cycle

Locations

Country	Name	City	State
United States	Norris Cotton Cancer Center	Lebanon	New Hampshire

Sponsors (2)

Lead Sponsor	Collaborator
Dartmouth-Hitchcock Medical Center	Hoffmann-La Roche

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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		3 weeks	Yes
Secondary	To determine the pharmacokinetic profile of capecitabine, 5-fluorouracil, and 5'-deoxy-5-fluorouridine following administration of docetaxel on day 8.		9 days	No
Secondary	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		9 days	No
Secondary	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		9 days	Yes

External Links

•   Norris Cotton Cancer Center Home Page