S5-5: A Phase III, Randomized, Double-Blind, Placebo-Controlled Registration Trial To Evaluate the Efficacy and Safety of Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Patients with Previously Untreated HER2−Positive Metastatic Breast Cancer (CLEOPATRA).
Authors: Baselga J , Kim S-B , Im S-A , Hegg R , Im Y-H , Roman L , Pedrini JL , Cortés J , Knott A , Clark E , Ross GA , Swain SM 
Published: June 2012

Abstract
Background: Pertuzumab (P) is a fully humanized investigational monoclonal antibody that binds to human epidermal growth factor receptor 2 (HER2), preventing dimerization of HER2 with other HER family members and inducing antibody-dependent cell-mediated cytotoxicity. Its mechanisms of action are complementary to those of the anti-HER2 antibody trastuzumab (H) and the two antibodies combined have superior activity compared with either antibody alone in preclinical and clinical studies. In patients with advanced disease, P in combination with H has been shown to be active in patients whose disease has progressed while on H therapy (Baselga et al. J Clin Oncol 2010). Furthermore, P has been shown to improve the activity of H and docetaxel (T) in a randomized neoadjuvant study (Gianni et al. SABCS 2010, S3-2). No increase in overall toxicity and, in particular, no increase in cardiac events was observed with the addition of P to H and HT regimens.
Methods: In this double-blind Phase III study patients with centrally confirmed HER2−positive metastatic or locally recurrent, unresectable breast cancer were randomized to receive either placebo+H+T or P+H+T. Patients could have received one prior hormonal treatment for metastatic breast cancer and/or prior systemic neoadjuvant or adjuvant therapy including prior H and T. Patients had to have a baseline left ventricular ejection fraction ≥50% and no history of declines to &lt;50% during or after prior H therapy.
Study medication was as follows: P 840 mg loading dose followed by 420 mg q3w; H 8 mg/kg loading dose followed by 6 mg/kg q3w; T 75 mg/m2 q3w (with subsequent dose escalation to 100 mg/m2 if 75 mg/m2 was well tolerated). Patients were recommended to receive at least 6 cycles of T. In the case of chemotherapy discontinuation due to cumulative toxicity, antibody therapy was continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Patients were stratified according to region and prior treatment status (adjuvant therapy or de novo metastatic breast cancer).
The primary endpoint for the study was progression-free survival (PFS) as determined by independent review. The primary analysis was planned to take place when approximately 381 independently confirmed PFS events had occurred. This would provide 80% power to detect a 33% improvement in PFS (HR=0.75) at the two-sided significance level of 5%. Secondary endpoints included overall survival, investigator-determined PFS, overall response rate, duration of response, safety, and quality of life.
Patient safety was monitored throughout the study by an independent data monitoring committee and a cardiac review committee.
This study is registered at ClinicalTrials.gov: NCT00567190.
Results: 808 patients were recruited between February 2008 and July 2010. The required number of PFS events for analysis of the primary endpoint has been reached and independent assessment PFS is currently being performed. Results of the primary analysis of efficacy and safety will be presented.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S5-5.