A randomized double-blind phase II study of the combination of oral WX-671 plus capecitabine versus capecitabine monotherapy in first-line HER2-negative metastatic breast cancer (MBC)

Autor: Bernhard Heinrich, Salomon M. Stemmer, Barbara Schmalfeldt, Paul Bevan, Nadia Harbeck, Lori J. Goldstein, Lisa Richters, Celia Tosello Oliveira, Sabine Kastner, C. Mala
Rok vydání: 2013
Předmět:
Zdroj: Journal of Clinical Oncology. 31:508-508
ISSN: 1527-7755
0732-183X
Popis: 508 Background: uPA and its inhibitor PAI-1 play a key role in tumor invasion, metastasis and tumor growth. uPA and PAI-1 are biomarkers validated at highest level of evidence in breast tumors and are recommended for clinical decision making by ASCO. WX-UK1 is a competitive inhibitor of uPA with an inhibition constant in the submicromolar range. WX-671 (upamostat) is an oral prodrug of WX-UK1. Methods: Female patients aged >18, with HER2 negative MBC were randomized in a double-blind fashion to receive upamostat (200 mg orally daily for 21 days) plus C (1000 mg/m2 orally twice daily for 14 days) vs. C (same regimen) in 3 week treatment cycles until progressive disease or unacceptable toxicity. 132 from five countries were enrolled. The primary objective was to evaluate the efficacy of the combination of upamostat and C compared to C alone by assessment of progression free survival (PFS). The study also evaluated the objective response rate and safety as well as pharmacokinetics (PK). Efficacy was evaluated by RECIST by independent central read. Results: Median treatment duration was 8 cycles in both arms. In the total study population (intent to treat; ITT) upamostat led to an increase of median PFS from 7.5 months (95% CI: 4.2; 12.8) in the control group to 8.3 months (95% CI: 5.6; 9.6) in the combination therapy. An unexpectedly high rate (50%) of study patients presented within their first two years after initial diagnosis. In patients who had received prior adjuvant chemotherapy, PFS improved from 4.3 months (95% CI: 2.6; 9.7) in the C alone group to 8.3 months (95% CI: 5.6; 10.9) in the upamostat plus C group. The overall response rate was higher in the combination group compared to C alone (20% vs. 12% at Week 24). PK analysis demonstrated no drug-drug interactions between upamostat and C. The combination therapy was safe and well tolerated. Conclusions: This is the first proof of efficacy of an anti-uPA therapy in breast cancer. The heterogeneity of the patients in this study may underestimate the potential treatment effects of upamostat. Additional subset analyses will be presented. Future biomarker-stratified strategies may reveal better efficacy. Clinical trial information: NCT00615940.
Databáze: OpenAIRE
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