OT1-01-04: NEO-ZOTAC: A Phase III Randomized Trial with Neoadjuvant Chemotherapy (TAC) with or without Zoledronic Acid for Patients with HER2−Negative Large Resectable or Locally Advanced Breast Cancer.
Authors: van de Ven S , Nortier JWR , Liefers GJ , ten Tije A , Kessels LW , van Laarhoven HWM , van Warmerdam LJC , Vriens B , van den Bosch J , van Meershoek-Klein Kranenbarg E , van Leeuwen E , Kroep JR 
Published: June 2012

Abstract
Background
The role of bisphosphonates (BPs) when added to the (neo) adjuvant treatment of breast cancer is still unknown. Adding the most potent BP zoledronic acid to neoadjuvant chemotherapy may lead to an improved clinical and pathological response in patients with breast cancer.
Trial design: After randomization, patients will be treated in arm A (experimental) or arm B (control group). Arm A: 6x TAC q 3 weeks with zoledronic acid; Doxorubicin 50 mg/m2 i.v. followed by Cyclophosphamide 500 mg/m2 i.v. and Docetaxel 75 mg/m2 i.v. on day 1, Pegylated G-CSF 6 mg once per cycle s.c on day 2, zoledronic acid 4 mg i.v in 15 minutes within 24 hours after infusion of chemotherapy. Arm B: 6x TAC q 3 weeks; Doxorubicin 50 mg/m2 i.v. followed by Cyclophosphamide 500 mg/m2 i.v. and Docetaxel 75 mg/m2 i.v. on day 1, Pegylated G-CSF 6 mg once per cycle s.c on day 2.
Eligibility criteria: Main inclusion criteria are large resectable or locally advanced breast cancer (T2,T3,T4, every N, M0), measurable disease, histological proven HER2−negative breast cancer, age ≥18 years, WHO 0–2, adequate bone marrow-, renal- and liver function, written informed consent. Main exclusion criteria are evidence of distant metastases (M1), history of breast cancer, prior breast surgery, prior chemotherapy or radiation therapy, previous malignancy within 5 years, prior bisphosphonate usage, peripheral neuropathy &gt; grade 2, current active dental problems.
Study endpoints: The primary endpoint of this study is the pathologic complete response (pCR) rate to neoadjuvant chemotherapy with or without zoledronic acid at surgery. Secondary endpoints are clinical response (RECIST 1.1), ER/PR and HER2 heterogeneity in core biopsy vs. operation specimen, toxicity, disease free survival and overall survival.
Optional side studies include fluorescent imaging (SoftScan®), changes in bone biochemical markers and the insulin-like growth factor (IGF) pathway, circulating tumor cells (CTC's) and circulating endothelial cells (CEC's), the false-negative rate of the sentinel node biopsy after neoadjuvant chemotherapy, single nucleotide polymorphisms (SNPs) and Ki-67, apoptotic index and IGF pathway in core biopsy and operation specimen.
Statistical Methods: This study is designed as a randomized, open-label, multi centre phase III trial. It is anticipated that using a 5% significance level based on the two-sided Fisher's exact test with a power of 80%, a total number of 250 patients (125 patients in each arm) are needed to show an improvement of the pCR rates from 17% in arm B to 34% in the experimental arm A. Randomization will be done according to the Pocock's minimization technique stratified by cT-classification, cN-classification and estrogen receptor status. The primary endpoint will be analyzed using the Cochran-Mantel-Haenszel test.
An interim efficacy analysis (analyzing pCR) after 100 operated patients is planned.
Accrual: Patients are currently being included from 27 centers in the Netherlands. Presently (16th June 2011) a total number of 116 patients have been included since start of the study (July 2010). The expected end of accrual of 250 patients will be the last quarter of 2012.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT1-01-04.