Design of RESILIENCE: A phase (Ph) III trial comparing capecitabine (CAP) in combination with sorafenib (SOR) or placebo (PL) for treatment (tx) of locally advanced (adv) or metastatic HER2-negative breast cancer (BC).

Abstract

TPS124 Background: SOR is an oral multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized Ph 2b screening trial (SOLTI 0701) that compared SOR+CAP vs PL+CAP in patients (pts) with adv BC demonstrated significant improvement in progression-free survival (PFS) for the SOR arm (median 6.4 vs 4.1 mo; hazard ratio=0.58; 1-sided P=0.0006). Most drug-related adverse events were grade 1/2 in severity with the exception of grade 3 hand-foot skin reaction/syndrome (HFSR/HFS) (44% in SOR+CAP vs 14% in PL+CAP). The SOLTI 0701 results suggest a role for SOR+CAP in the tx of BC and warrant confirmation in a Ph 3 trial. Methods: RESILIENCE is an ongoing double-blind, randomized Ph 3 trial designed to compare SOR+CAP vs PL+CAP in adv HER2-negative BC. Eligibility criteria include: ≥18y of age; ≤1 prior chemotherapy regimen for adv BC; and resistant to/failed taxane and anthracycline or no indication for further anthracycline. Prior hormonal or radiation tx is allowed, but prior VEGF tx is not. Pts with significant cardiovascular disease or active brain metastases are not eligible. Pts are stratified by hormone receptor status, geographic region, and prior chemotherapy for adv BC (Y/N) and randomized (1:1) to CAP (1000 mg/m2 po twice daily [BID], days 1–14 of 21) in combination with SOR (po BID, days 1–21, total dose 600 mg/day) or matching PL. CAP and SOR/PL doses can be escalated to 2500 mg/m2 per day and 800 mg/day, respectively, as tolerated, or reduced to resolve toxicity but dose re-escalation is not allowed. Guidelines are provided for prophylactic and symptomatic tx of HFSR/HFS. Radiographic assessment is every 6 wk for the first 36 wk, and every 9 wk thereafter. The primary endpoint is PFS. Secondary endpoints include overall survival, time to progression, overall response rate, duration of response (RECIST 1.1 criteria), and safety. Enrollment began in Nov 2010 with a target of ~519 pts. The trial is registered at ClinicalTrials.gov (NCT01234337). Conclusions: RESILIENCE will provide definitive PFS data for SOR+CAP in adv HER2-negative BC and better characterize the benefit-to-risk profile.