Phase I-II Study to Evaluate Safety, Efficacy and Pharmacokinetic Interactions Between Capecitabine (XELODA) and Exisulind (APTOSYN) in Patients With Metastatic Breast Cancer
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
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Blood tests done every week for first 6 weeks.
Lajos Pusztai, MD, DPHIL
UT MD Anderson Cancer Center
United States: Food and Drug Administration
|University of Texas M. D. Anderson Cancer Center||Houston, Texas 77030|