Design of RESILIENCE: a phase 3 trial comparing capecitabine in combination with sorafenib or placebo for treatment of locally advanced or metastatic HER2-negative breast cancer

Abstract

Introduction A double-blind, randomized, phase 2b screening trial (SOLTI-0701) of sorafenib, an oral multikinase inhibitor, in patients with HER2-negative advanced breast cancer (BC), showed a statistically significant improvement in progression-free survival (PFS) in the sorafenib + capecitabine arm versus the placebo + capecitabine arm: 6.4 versus 4.1 months (hazard ratio = 0.58; one-sided P = 0.0006). Grade 3/4 toxicities were comparable except G3 hand-foot skin reaction/ syndrome (HFSR/HFS) (44% vs. 14%). These results support a phase 3 trial of sorafenib + capecitabine in advanced BC. Methods RESILIENCE is an ongoing multinational, double-blind, placebo-controlled, phase 3 trial designed to assess sorafenib + capecitabine as first-line or second-line therapy in advanced HER2- negative BC (ClinicalTrials.gov, NCT01234337). Eligibility criteria include: <18 years of age; <1 prior chemotherapy regimen for advanced BC; resistant to/failed taxane and anthracycline or no indication for further anthracycline; no prior VEGF treatment. Patients are randomized to capecitabine (1,000 mg/m 2 p.o. twice daily, days 1 to 14 of 21) with sorafenib (p.o. twice daily, days 1 to 21, total dose 600 mg/day) or placebo. Sorafenib 600 mg/day corresponds to the average daily dose during SOLTI-0701 that was effective and manageable. Doses can be escalated to 2,500 mg/m 2 and 800 mg/day or reduced to manage toxicity. Dose re-escalation after reduction is only allowed for sorafenib/ placebo. Guidelines detail prophylactic and symptomatic therapy for HFSR/HFS. Radiographic assessment is every 6 weeks for 36 weeks, then every 9 weeks. The primary endpoint is PFS. Secondary endpoints include overall survival, time to progression, overall response rate, and duration of response. Enrollment began in November 2010 and targets ~519 patients. Conclusion RESILIENCE will provide definitive PFS data for sorafenib + capecitabine as first-line or second-line therapy in HER2-negative advanced BC and will better characterize the benefit-to-risk profile of this regimen.