Journal of Clinical Oncology, Vol 21, Issue 18
(September), 2003: 3454-3461
© 2003 American Society for Clinical Oncology
Phase I and II Study of Exisulind in Combination With Capecitabine in Patients With Metastatic Breast Cancer
Lajos Pusztai,
Jim Hou Zhen,
Banu Arun,
Edgardo Rivera,
Clark Whitehead,
W. Joseph Thompson,
Kimberly M. Nealy,
Amy Gibbs,
W. Fraser Symmans,
Francisco J. Esteva,
Daniel Booser,
James L. Murray,
Vicente Valero,
Terry L. Smith,
Gabriel N. Hortobagyi
From the Departments of Breast Medical Oncology, Department of Biostatistics, and the Division of Medicine and Pathology of the University of Texas M.D. Anderson Cancer Center, Houston TX; and Cell Pathways Inc, Horsham, PA.
Address reprint requests to Lajos Pusztai, MD, PhD, Box 424, Department of Breast Medical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009; e-mail: lpusztai{at}mdanderson.org.
Purpose: We studied the safety and clinical activity of exisulind in combination with capecitabine in 35 patients with metastatic breast cancer (MBC).
Patients and Methods: All patients had received previous anthracycline and taxane chemotherapies. Two dose levels of exisulind were explored, 125 and 250 mg orally bid as continuous daily therapy, concomitant with capecitabine 2,000 mg/m2 for 14 days in 21-day cycles. In the phase I study, the dose-limiting toxicities were hand-foot syndrome and diarrhea. The 125-mg bid dose was selected for phase II testing.
Results: The most common nonhematologic grade 2 to 3 adverse events were hand-foot syndrome (57%) and fatigue (48%). The most frequent grade 2 to 3 laboratory abnormality was granulocytopenia. No death, unexpected adverse events, or cumulative toxicity were encountered. One complete and four partial responses were achieved (objective response rate, 16%) in the 31 patients assessable for response. The median duration of response was 31 weeks; three patients experienced stable disease longer than 26 weeks. Overall clinical benefit (complete response, partial response, or stable disease > 26 weeks) was 23%. Fourteen specimens were available for immunohistochemical assessment of phosphodiesterase-5 isoenzyme (PDE-5) and PDE-2 expression, which are the targets of exisulind. Eighty percent of tumors showed some expression of PDE-5 in the invasive cancer cells including 35% that showed moderate or strong staining. PDE-2 showed moderate or strong staining in 78% of tumors. There was no apparent association between tumor response and staining intensity.
Conclusion: Exisulind (125 mg orally bid) in combination with capecitabine is well tolerated and the combination has anticancer activity similar to that of capecitabine alone in heavily pretreated patients with MBC.
Supported by Cell Pathways Inc, Horsham, PA.
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