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

Phase 1

Completed

• Conditions: Breast Neoplasms; Metastases, Neoplasm
• Interventions: Drug: Capecitabine; Drug: Exisulind

• Registration Number: NCT00037609
• Lead Sponsor: M.D. Anderson Cancer Center

Brief Summary

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.

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 Timeline

• Study Start: 2001-01
• Study First Submitted: 2002-05-17
• Study First Submitted QC: 2002-05-17
• Study First Posted: 2002-05-20
• Primary Completion: 2003-02
• Study Completion: 2003-02
• Status Verified: 2012-10
• Last Update Submitted: 2012-10-22
• Last Update Posted: 2012-10-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 35

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Capecitabine + Exisulind	Capecitabine	Capecitabine 1000 mg/m\^2 taken by mouth twice daily. Exisulind 125 mg taken by mouth twice daily.
Capecitabine + Exisulind	Exisulind	Capecitabine 1000 mg/m\^2 taken by mouth twice daily. Exisulind 125 mg taken by mouth twice daily.

Primary Outcome Measures

Name	Time	Method
Response Rate	Blood tests done every week for first 6 weeks.

Trial Locations

Locations (1)

University of Texas M. D. Anderson Cancer Center; 🇺🇸 Houston, Texas, United States