A Phase 1/2 interventional study of Capecitabine and Exisulind in Breast Neoplasms and Metastases, Neoplasm, sponsored by M.D. Anderson Cancer Center. Completed at 1 site in United States. Per ClinicalTrials.gov, last updated 2012-10-24.
Sponsored by M.D. Anderson Cancer Center · Phase 1/2, Interventional, and Treatment
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.
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.
12,544 studies on the registry are indexed under Breast Neoplasms; 2,892 are open to participants now.
This study's enrollment of 35 is below the median of 72 across 9,303 interventional studies indexed under Breast Neoplasms.
Browse Breast Neoplasms studies →M.D. Anderson Cancer Center is the lead sponsor of 2,999 studies on the registry; 581 are open to participants now.
Of its 599 completed or terminated interventional studies of FDA-regulated products, 402 (67%) have results posted.
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Each patient must meet all these criteria in order to be considered for enrollment in the Phase I study:
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:
Capecitabine 1000 mg/m\^2 taken by mouth twice daily. Exisulind 125 mg taken by mouth twice daily.
Drug: Capecitabine · Drug: Exisulind
1000 mg/m\^2 taken by mouth twice daily.
Also known as: Xeloda
125 mg taken by mouth twice daily.
Also known as: Aptosyn
Response Rate
Time frame: Blood tests done every week for first 6 weeks.
This study is completed, as verified in Oct 2012. You cannot join it, but the record below documents what was studied.
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M.D. Anderson Cancer Center