Geparquinto: First Planned Safety Analysis on 60 Patients with HER2 Negative Primary Breast Cancer Receiving Neoadjuvant Chemotherapy ± Bevacizumab or ± RAD001 (GBG 44).
Authors: G. von Minckwitz, I. Bauerfeind, B. Gerber, J. Huober, H. Eidtmann, C. Solbach, H. Tesch, S. Loibl, V. Nekljudova, M. Untch
Journal: Cancer Research (2009)

Abstract Background:New targeted agents are investigated in neoadjuvant trials to estimate rapidly the potential efficacy of these drugs in early stage breast cancer. Patients (pts) without mid course response are in need for improved therapy. As the tolerability of these new treatment combinations is unknown, an internal pilot phase for safety was incorporated into the phase III GeparQuinto trial with an antiangiogenic treatment and RAD001 for HER2neg primary breast cancer pts.Patients and Methods:In the GeparQuinto trial with a planned overall sample size of 2500 pts we examine the additive effect of bevacizumab (BEV) to EC – docetaxel (DOC) on pathological complete response. Pts not responding to EC ± BEV are considered to be chemo-resistant. To overcome drug resistance, these non-responding pts were randomized to weekly paclitaxel (PAC) ± RAD (Everolimus; RAD001). Female pts with untreated, histologically confirmed uni- or bilateral, cT3/4a-d, HER2– breast cancer and no clinically relevant cardiovascular co-morbidities are randomized to 4 cycles of E (90mg/m²) + C (600 mg/m²) q3w ± BEV (15 mg/kg i.v.) q3w. After 4 cycles, the response was evaluated. Pts with response continue with DOC (100mg/m²) ± BEV (15mg/kg) q3w. If the tumor size did not decrease by ≥50%, pts were randomized to PAC (80mg/m² weekly) ± RAD (5mg orally daily, starting with a dose escalation over 14 days and 7-14 days prior the first PAC infusion) for 12 weeks. Surgery was performed in all pts after total treatment duration of 24 weeks. Grade 3+4 toxicities of the first cycle EC ± BEV, DOC ± BEV and PAC ± RAD was monitored for 20, 40, 60 P and an interim safety analysis was performed when 60 pts completed all cycles.Results:Of the 60 HER2 neg pts, 30 received 4xEC, 30 4xEC+BEV. 40 responders continued treatment with DOC (N=21) and DOC+BEV (N=19). 20 non-responders were randomized to PAC (n= 9) and PAC+RAD (n= 11). 2 pts discontinued treatment early.Premature treatment discontinuation was observed in 12 of 60 pts [during EC (2x), DOC (3x), DOC+BEV (1x), PAC (4x) and PAC+RAD (2x)], but only in 6 pts due to toxicity [DOC (2x); DOC+BEV (1x); PAC (3x)]. Other reasons were protocol violation (1x), incompliance (1x), progress [EC (1x), DOC (1x), PAC (2x)].BEV increased only the rate of leucopenia grade (gr) 3-4 during EC [gr 1-4 (3-4): –BEV: 93.8 % (40.6%) vs. +BEV: 90% (70.0%); p=0.666 (0.024)] and of mucositis during DOC [gr 1-4 (3-4): –BEV: 52.4% (9.5%) vs. +BEV: 100% (36.8%); p&amp;lt;0.0001 (0.06)]. RAD increased the rate of neutropenia during PAC [gr 1-4 (3-4): –RAD: 11.1% (0.0%) vs. +RAD: 80.0% (10.0%); p=0.005 (1.0)]. No significant differences were found for other hematologic and non-hematologic toxicities.Conclusion:The addition of BEV to EC-DOC was considered safe and the pilot phase was terminated. Safety data from all 60 pts treated with PAC ± RAD will be presented at the meeting. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1096.