Abstract OT3-1-01: A two-cohort, phase II, cardiac safety study of pertuzumab, trastuzumab, and neoadjuvant anthracycline-based chemotherapy in patients with HER2-positive, locally advanced, inflammatory, or early breast cancer
Authors: Swain Sandra M , Ewer Michael S , Douthwaite Hannah , Szado Tania , Waldron-Lynch Maeve , Dang Chau 
Published: May 2015

Abstract
Background: In HER2-positive early breast cancer (BC), neoadjuvant pertuzumab (P) + trastuzumab (T) + docetaxel (D) significantly increased pathologic complete response (pCR) rates compared with T+D (Gianni L, et al. Lancet Oncol 2012); high pCR rates were also seen with P+T in combination with anthracycline- and non-anthracycline-based regimens (Schneeweiss A, et al. Ann Oncol 2013). Neoadjuvant P+T + chemotherapy was well tolerated, with little increased toxicity associated with the addition of P. Although there was a higher rate of cardiac adverse events (AEs), left ventricular systolic dysfunction (LVSD), and left ventricular ejection fraction (LVEF) declines in P+T-containing arms compared with arms without P, these events were generally asymptomatic, reversible, and patients (pts) recovered with no sequelae. No data are available for neoadjuvant P-based regimens that include paclitaxel (Ptx) and dose-dense doxorubicin plus cyclophosphamide (ddAC), despite these being widely used in (neo)adjuvant BC therapy. This study will evaluate the cardiac safety of two anthracycline-based neoadjuvant regimens in combination with P+T. Following surgery, all pts will receive adjuvant P+T.
Trial design: In this non-randomized, open-label, phase II study, two parallel cohorts of pts receive different P-based neoadjuvant treatment regimens. In Cohort A, pts receive four 2-weekly cycles of ddAC, followed by 12 doses of weekly Ptx, plus four 3-weekly (q3w) cycles of P+T from the start of Ptx. In Cohort B, pts receive four q3w cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, followed by four q3w cycles of D, plus four q3w cycles of P+T from the start of D. Following surgery, both cohorts receive 13 cycles of P+T.
Eligibility: Pts with HER2-positive, locally advanced, inflammatory, or early BC (size &gt;2 cm or &gt;5 mm and node-positive) are eligible if they have a baseline LVEF ≥55% and an ECOG performance status ≤1. Among the exclusion criteria are prior incisional biopsy or excision of the primary tumor, prior systemic or radiation therapy for cancer, and prior chemopreventive agents. Pts are also excluded if they have poorly controlled hypertension, angina requiring medication, a history of congestive heart failure, serious or uncontrolled cardiac arrhythmia requiring treatment, or myocardial infarction within 6 months prior to enrollment.
Aims: The primary objective is cardiac safety during the neoadjuvant period, assessed by incidence of symptomatic LVSD and LVEF changes. Secondary objectives include cardiac safety in the adjuvant and post-treatment periods, incidence of all AEs, pCR rate, event-free survival, invasive disease-free survival, and overall survival.
Statistical methods: No statistical hypothesis testing will be performed. Safety and efficacy results will be summarized descriptively. A sample size of 200 pts per cohort is expected to provide sufficient data to evaluate the cardiac safety of each regimen with acceptable precision (exact Clopper-Pearson 95% CIs) around the expected rates.
Accrual: The first patient in is planned for August 2014.
Citation Format: Sandra M Swain, Michael S Ewer, Hannah Douthwaite, Tania Szado, Maeve Waldron-Lynch, Chau Dang. A two-cohort, phase II, cardiac safety study of pertuzumab, trastuzumab, and neoadjuvant anthracycline-based chemotherapy in patients with HER2-positive, locally advanced, inflammatory, or early breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-1-01.