Interim Results of BACH: Randomized Phase II Trial Evaluating the Safety of Two Chemotherapy Regimens as Adjuvant Therapy in Patients with HER2-Positive Breast Cancer: PLD + Cyclophosphamide + Trastuzumab (PLD+C+H), or Doxorubicin + Cyclophosphomide (A+C), Each Followed by Paclitaxel + Trastuzumab (T+H).

Abstract Background: For patients with HER2+ breast cancer AC + H results in unacceptable cardiotoxicity requiring sequential administration. Substituting pegylated liposomal doxorubicin (PLD) for doxorubicin in an adjuvant regimen may minimize the risk of cardiotoxicity and permit earlier integration of adjuvant H. Methods: In this multinational, open-label, parallel group trial, women ≥18 y with resected LN+, or high-risk LN- HER2+ breast cancer, were stratified by age (<55; ≥55 y) & randomized in a 1:2 ratio to: Arm A: A 60mg/m2 +C 600mg/m2 q21d x 4 (12 wk) followed by weekly T 80mg/m2 +H 2mg/kg (first dose 4mg/kg) x 4 (12 wk) or Arm B: PLD 35mg/m2 +C600 mg/m2 q21d + weekly H 2mg/kg (first dose 4mg/kg) x 4 (12wk), followed by weekly T 80mg/m2 + H2mg/kg x 4 (12wk). Subsequent treatment was H for a total of 1 y administered at investigator discretion. Primary objective was to determine the overall incidence of level 1 (cardiac death or severe heart failure with left ventricular ejection fraction (LVEF) drop >10% to <50%) and level 2 (asymptomatic or mildly symptomatic with LVEF drop >10% to <50%) cardiac events during the 8 cycles of chemotherapy. This planned interim analysis reports on the first 90 of the accrued 180 pts completing 8 cycles of protocol treatment. The trial would be stopped by the IDMC if ≥ 10/60 pts in Arm B experienced an event during the 8 cycles of chemo+H. Results: Between 08/2007 and 08/2008 60 pts were randomized to Arm B and 30 to Arm A. 58 pts from Arm B were eligible for cardiac toxicity assessment (modified ITT). Baseline characteristics including age, BSA, ECOG status and NYHA class were balanced. No level 1 or level 2 cardiotoxic events were observed (0.0%; 95% CI: 0.0-6.2 vs 0.0%; 95% CI: 0.0-11.6). There was a significant reduction in LVEF in arm A from baseline to the end of cycle 8 (p=0.017). The change in LVEF in arm B was not statistically significant (p=0.058). Adverse events included (Arm B vs A) Grade 1-4 alopecia (52.5% vs 76.7%), palmar-plantar erythrodysaesthesia (PPE, 59.3% vs 3.3%), fatigue (50.8% vs 73.3%), rash (32.2% vs 6.7%), mucositis (33.9% vs 26.7%), nausea (54.2% vs 63.3%), diarrhea (37.3% vs 20.0%), stomatitis (32.2% vs 20.0%), cough (16.9% vs 36.7%) and myalgia (22.0% vs 30.0%). 8 (13.6%) vs 3 (10%) pts (Arm B vs A) experienced serious adverse events.ResultsArm B (N=58)Arm A (N=30)LVEF Baseline %: Mean (SD)64.5 (6.92)65.5 (6.38)Cycle 5 (Week 13) %: Mean (SD)62.1 (4.85)63.3 (4.61)End of Cycle 8 (Week 25) %: Mean (SD)61.6 (7.30)60.3 (5.59)Cardiac toxicity rate Level 1 Cardiac Events: % (CI)0.0 (0.0, 6.2) *0 .0(0.0, 11.6) *Level 2 Cardiac Events: % (CI)0.0 (0.0, 6.2)0 .0(0.0, 11.6)* Confidence interval is computed using the exact binomial method.Conclusions: Concomitant PLD+C+H as adjuvant therapy for HER-2+ breast cancer did not result in an increased cardiac events rate based on this interim analysis. The study completed accrual April 2009 and final analysis is planned mid-2010. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2085.

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