Phase I-II study to evaluate safety and efficacy of capecitabine (Xeloda) and exisulind (Aptosyn) combination therapy in patients with metastatic breast cancer

Exisulind is a selective inducer of apoptosis in neoplastic cells and also potentiates the cy totoxic activity of chemotherapy drugs in preclinical models. The primary objective of the phase I part of this study was to determine a safe dose for combination therapy with capecitabine (C) and exisulind (E) in patients with metastatic breast cancer who failed both anthracycline and taxane chemotherapy. Phase I results are reported here. Design: Two dose levels were tested; level 1, C 1000 mg/m2 po BID × 14 days + E 125 mg po BID and level 2, C 1000 mg/m2 po BID × 14 days + E 250 mg po BID daily in 21-day cycles. The first cohort of 5 patients was entered at dose level 1. If no dose-limiting toxicity (DLT, > 33% of non-hematologic grade >3 or hematological grade 4 toxicity) was seen after the first cycle, then the second cycle was given at dose level 2. If > 3 patients were eligible for dose escalation, then additional 5 patients were accrued to start therapy at dose level 2. Dose modification for C followed the package insert. E was to be reduced only for > grade 2 liver toxicity or prolonged non-hepatic toxicity. Results; Thirteen patients were accrued and completed at least 1 full cycle. Three of 5 patients in the first cohort were advanced to dose level 2 and 8 additional patients were accrued to start treatment at level 2. Twenty-two cycles, 7 at dose level 1 and 15 at dose level 2 were given. Six (54% ) of the 11 patients at level 2 required dose reduction. Three patients for > grade 2 reversible liver enzyme elevation assumed to be related to E, 6 for C-related toxicity and 2 patients had toxicity from both. DLT were grade 3 hand-foot syndrome and diarrhea. Grade 2 fatigue, nausea and myalgia was also reported. No grade > 3 hematological toxicity was seen. Of the 9 patients who completed 2 cycles of therapy, 4 had stable disease and 5 progressed. Conclusion: No unexpected toxicity was seen. Treatment at dose level 2 resulted in significant toxicily, all symptomatic adverse events were consistent with toxicity from capecitabine. Currently patients are accrued at level 1 to explore toxicity and efficacy of this combination further.