1067 Background: The pro-drug capecitabine is approved in anthracycline- and paclitaxel-resistant MBC. However, GI/skin toxicity and wide interpatient PK variability occur despite body surface area (BSA)-dosing schedule. We hypothesized that a fixed-dose schedule would simplify drug administration and provide an effective and safe alternative to BSA-based dosing.
METHODS
We conducted an open label, single-arm, two-stage study of oral capecitabine with fixed starting dose (1.5 g PO bid x 14d q21d) in patients treated with max 3 prior MBC cytotoxic regimens. Blood samples obtained were PG at baseline and PK during cycle 1. We correlated pharmacodynamic (PD) endpoints (e.g., efficacy [response] per RECIST and toxicity, adherence (MEMS caps) and PK/PG.
SAMPLE SIZE
45 patients to detect 25% response rate from null response rate of 10% using Simon two-stage design with 80% power and 5% type I error rate. Three responses were required in 1st stage to proceed to 2nd.
RESULTS
Twenty six patients were enrolled in the first-stage and 21 were evaluable (57% ER+, 43% ER-; 14% also HER2+); median BSA 1.89 m2; median # prior chemo = 0, range 0-2) after a median of 4 cycles of capecitabine (range 2-16). Median ratio of fixed administered dose vs BSA-dosing was 79% (range 68-92%). Eight patients had stable disease but progressed after median of 7 cycles (range 2-16). Despite clinical benefit rate of 19% (4 patients with SD ≥ 24 weeks), no partial or complete responses were observed following the 1st stage and study was closed. No unexpected related toxicities were seen except for grade 2 hand-foot syndrome (28%) and vomiting (5%) requiring dose-reduction. We observed a significant variability of the active metabolite 5-fluorouracil (5FU) Cmax and AUC (154% vs 85% in historical controls), which was not explained by BSA (P>0.05).
CONCLUSIONS
Fixed-dose capecitabine is feasible, simplifies drug administration, and is associated with PK variability of 5FU not explained by BSA. Single agent activity of capecitabine was modest in our patients with ER- or ER+ endocrine-resistant disease and comparable to recent studies. Final PK/PD/PG analyses will be reported. (Funding from Roche and Susan G. Komen for the Cure.).