Combination therapy with gefitinib and capecitabine in metastatic breast cancer (MBC): A phase I trial

Abstract

10564 Background: Preclinical models have suggested synergy between the EGFR tyrosine kinase inhibitor gefitinib (G) and the 5-FU prodrug capecitabine (C), an active treatment for MBC. This phase I study was designed to explore the safety of this all-oral regimen in patients (pts) with MBC. Methods: Pts were treated in sequential cohorts (n = 3–6) using a fixed dose of G (250 mg qd continuously) and escalating doses of C (1500 mg/m2/day, 1750 mg/m2/day, and 2000 mg/m2/day) in a 21-day cycle. An additional 10 pts were enrolled in a validation cohort at the maximum tolerated dose (MTD). Dose limiting toxicity (DLT) was defined during the first cycle as any grade 3/4 toxicity or a delay >3 weeks due to unresolved toxicity. The primary endpoint was safety; secondary endpoints included assessments of tumor response (using RECIST criteria), adherence to the oral regimen, and biomarker measurements. Results: 19 pts were enrolled; the mean age was 49 y, 58% of tumors were hormone receptor positive, and 10% were HER2 positive. The mean number of prior MBC chemotherapy regimens was 1.2 and 74% had visceral spread. No pts in dose escalation cohorts had DLT during cycle 1. The 10 pts in the validation cohort (MTD C 2000 mg/m2) had 3 DLTs in cycle 1 and 1 DLT in cycle 2 (95% CI 12–74%). For all pts at C 2000 mg/m2 (n = 13), there was no grade 4 toxicity, however 5 (38%) had grade 3 toxicity, 7 (54%) required a C dose reduction, and 2 (15%) came off study for persistent toxicity. 3 pts (23%) experienced grade 3 diarrhea, and 4 pts (31%) had moderate to severe hand/foot syndrome. There were no objective responses (PR or CR) observed out of 18 evaluable pts. The mean number of completed cycles of therapy was 4.8, and 3 pts (16%) were treated for > 24 weeks. An exploratory analysis of serum EGFR measurements demonstrated no association of pre- or post-therapy values with lack of progression. Monitoring adherence to oral therapy using a microelectronic monitoring system (MEMS) was feasible, and detailed data will be presented. Conclusions: In this phase I dose escalation trial of G/C therapy in women with MBC, treatment was generally well tolerated, with a confirmed C MTD of 2000 mg/m2. Moderate toxicity and dose reductions were common. In this small cohort, the G/C combination did not appear to have substantial anti-tumor activity. [Table: see text]