Safety, Efficacy and Pharmacokinetic Between Capecitabine and Exisulind in Metastatic Breast Cancer Patients

October 22, 2012 updated by: M.D. Anderson Cancer Center

Phase I-II Study to Evaluate Safety, Efficacy and Pharmacokinetic Interactions Between Capecitabine (XELODA) and Exisulind (APTOSYN) in Patients With Metastatic Breast Cancer

The primary objective of the phase I study is to determine a safe dose for combination therapy with capecitabine and exisulind. A secondary objective is to assess pharmacokinetic interactions between the two drugs and assess the biological activity of exisulind.

The primary objective of the Phase II part of this study is to assess the anti-tumor activity of this combination therapy measured by objective tumor response. Secondary end points also assessed will be toxicity of therapy, duration of response and time to progression.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Rationale for this study:

Capecitabine is approved by the Food and Drug Administration (FDA) as 2nd or 3rd line chemotherapy for patients with metastatic breast cancer who previously have failed both anthracycline and taxane chemotherapy. Capecitabine produces objective tumor response of around 20% with a median duration of response of 32 weeks in these patients (1). These results indicate that improvements in the treatment of anthracycline and taxane resistant breast cancer are needed. Exisulind (sulindac sulfone, FGN-1, APTOSYNTM) is a sulfone metabolite of sulindac, a widely used nonsteroidal anti-inflammatory (NSAID) drug. Sulindac sulfone lacks inhibitory activity on the two isoforms of cyclooxygenase, COX 1 and COX 2, and is devoid of gastrointestinal and renal toxicity that is associated with NSAIDs. Exisulind selectively stimulates programmed cell death in a variety of neoplastic cells including colon, prostate, and mammary epithelial cells without affecting normal cells (2,3). Exisulind inhibits the growth of breast cancer cell lines in vitro and also inhibits chemically-induced mammary carcinogenesis in rats (4,5). The drug is also synergistic with a diverse group of cytotoxic compounds including cisplatin, taxanes and retinoids (6). Exisulind exerts its effects by inhibiting a novel phosphodiesterase that belongs to the PDE5 family which specifically degrades cGMP (7). Inhibition of this enzyme results in a rise in intracellular cGMP levels and leads to apoptosis through yet unknown mechanism. Exisulind also inhibits transcription factor NF-kB (8). The NF-kB pathway is activated by cellular stress including exposure to inflammatory cytokines, cytotoxic agents and oxidative stress (9). It is believed that activation of NF-kB protects from cell death, therefore, inhibition of this transcription factor may contribute to the proapoptotic, chemotherapy potentiating effect of exisulind.

Exisulind selectively promotes apoptosis in neoplastic cells whereas chemotherapeutic drugs induce programmed cell death in a non-selective manner. We hypothesize that combination of the 2 drugs will increase response rates by selectively augmenting the cytotoxic activity of chemotherapy. Furthermore, continuous maintenance treatment, between chemotherapy doses, with a minimally toxic drug that selectively induces apoptosis of cancer cells may improve response duration and ultimately may translate into improved survival and better quality of life. Each drug alone has an established maximum tolerated dose in humans. However, the combination of exisulind and capecitabine has not been tested. This phase I-II study is proposed to test safety and efficacy of this combination in patients with metastatic breast cancer.

Study Type

Interventional

Enrollment (Actual)

35

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • Houston, Texas, United States, 77030
        • University of Texas M. D. Anderson Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria

Each patient must meet all these criteria in order to be considered for enrollment in the Phase I study:

  • Histologically confirmed breast cancer and either clinical, radiological or laboratory evidence of metastatic disease.
  • Patients must have received both anthracycline-containing and taxane chemotherapy either as adjuvant treatment or therapy for metastatic breast cancer.
  • There is no limit on prior chemotherapy regimens or hormonal therapies received.
  • Concomitant bisphosphonate treatment is allowed for patients with bone metastases.
  • Patients must have recovered from acute toxic effects of any prior therapy including surgery and radiation.
  • Zubrod performance status < 2. (See Appendix A)
  • Adequate bone marrow function: platelets > 100,000/mm3, ANC > 1500 cells/mm3, hemoglobin > 8g/dl.
  • Normal renal function: creatinine < 2.0 mg/dl.
  • Adequate liver function: Bilirubin < 1.5 mg/dL. Transaminases (SGOT) or LDH, and alkaline phosphatase must be <1.5 x of the upper limit of normal in the absence of bone or liver metastasis, or <2.5 x of the upper limit of normal in the presence of radiologically apparent liver metastasis or bone metastasis, respectively.
  • Female patients must be of non-childbearing potential or non-lactating and using adequate contraception. Beta-HCG will be checked in premenopausal patients if clinically indicated.
  • Patients with brain metastases whose disease remained stable for more than 6 months after completing therapy to the brain are eligible.
  • Written informed consent.

In addition to the above, patients participating in the Phase II portion of this study:

Must have bidimensionally measurable or evaluable disease. Lytic lesions seen on plain radiographs will be considered evaluable in conjunction with bone scan abnormalities. Bone scan abnormalities alone, pure blastic bone metastases or irradiated lesions are not considered measurable or evaluable and will not be accepted. Also, pleural or peritoneal effusions will not be considered evaluable disease.

Exclusion Criteria

A patient must not be enrolled if any of the following criteria applies:

  • Known hypersensitivity to sulindac (CLINORIL).
  • Known hypersensitivity or contraindications to capecitabine (XELODAR) including prior therapy with capecitabine.
  • Clinical or laboratory evidence of significant liver disease.
  • Concomitant treatment with cytotoxic agents other than capecitabine or participation in any other investigational study.
  • Uncontrolled psychiatric, or social (addictive) disorders that would preclude obtaining informed consent or patient participation in the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Capecitabine + Exisulind
Capecitabine 1000 mg/m^2 taken by mouth twice daily. Exisulind 125 mg taken by mouth twice daily.
Drug: Capecitabine
1000 mg/m^2 taken by mouth twice daily.
Other Names:
  • Xeloda
Drug: Exisulind
125 mg taken by mouth twice daily.
Other Names:
  • Aptosyn

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Response Rate
Time Frame: Blood tests done every week for first 6 weeks.
Blood tests done every week for first 6 weeks.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

M.D. Anderson Cancer Center

Collaborators

Cell Pathways

Investigators

  • Study Chair: Lajos Pusztai, MD, DPHIL, UT MD Anderson Cancer Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2001

Primary Completion (Actual)

February 1, 2003

Study Completion (Actual)

February 1, 2003

Study Registration Dates

First Submitted

May 17, 2002

First Submitted That Met QC Criteria

May 17, 2002

First Posted (Estimate)

May 20, 2002

Study Record Updates

Last Update Posted (Estimate)

October 24, 2012

Last Update Submitted That Met QC Criteria

October 22, 2012

Last Verified

October 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ID00-049

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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