Abstract OT1-1-10: CirCe T-DM1 phase II trial: Assessing the relevance of HER2-amplified circulating tumor cells as a tool to select HER2-negative metastatic breast cancer for treatment with T-DM1
Authors: Bidard F-C , de Rycke Y , Asselain B , Dieras V , Lebofsky R , Pierga J-Y 
Published: August 2014

Abstract
Background: T-DM1 has demonstrated its efficacy in the second line of HER2-positive metastatic breast cancer patients. Several studies reported that some breast cancers considered as HER2-negative do have HER2-positive circulating tumor cells (CTC). Our previous report (Lightart & Bidard, Ann Oncol 2013) showed that the reliability of such discrepancy between primary tumor and CTC is directly related to the number of CTC analyzed. This study aims at studying the efficacy of T-DM1 in this setting.
Trial design: CirCe T-DM1 is a single arm two-step phase II multicenter study with adaptive design. Patients with HER2-negative measurable metastatic breast cancer will be screened by the FDA-approved CellSearch system, before the start of a second line treatment. HER2/CEP17 ratio will be quantified by FISH on CTC (Veridex). Patients with non HER2-amplified CTC or no CTC will be excluded from the study. Patients with HER2-amplified CTC will be treated by T-DM1 (Roche) single agent q3w, in either cohort “L” (low count: 1 to 4 HER2-amplified CTC) or in cohort “H” (high count: 5 or more HER2-amplified CTC). 14 patients (7L+7H) will be included in the first step. If needed, the second step will include 14 additional patients (7L+7H). Tumor response (per RECIST criteria) is the main objective of the trial.
Eligibility criteria: main criteria are HER2-negative metastatic breast cancer; measurable disease progressing after a first line treatment; PS 0-1; criteria related to T-DM1 treatment and ethics. Only patients with HER2-positive CTC will be treated by t-DM1.
Specific aim: this study will assess the response rate to T-DM1 in patients with HER2-amplified CTC and HER2-negative metastatic breast cancer, taking into account the number of HER2-amplified CTC detected (1-4 or 5+).
Statistical methods: To design this adaptive study, response rates were estimated to be H0 = 5% (no efficacy of T-DM1) and H1 = 25% (efficacy of T-DM1). After the first step (N = 7L and 7H patients): if no response is seen, the trial will be stopped, and considered as negative; if 3 or more responses are seen, we will conclude that the CTC FISH test is relevant to select patient for T-DM1 treatment, in either the L or/and H population, according to the observed pattern of responses; if 1 or 2 responses are observed, 14 more patients will be enrolled (7L+7H) in the second step of the trial. At the end of the second step, if 3 or less responses are observed, the trial will be considered as negative; if 4 or more responses are seen, we will conclude that the CTC FISH test is relevant to select patient for T-DM1 treatment, in either the L or/and H population, according to the observed pattern of responses. Based on the above-mentioned hypotheses and number of patients, the alpha risk was simulated to be of 6%, with a power of 94%.
Present accrual and target accrual: trial will start in summer 2013 in France. Up to 28 patients will be treated in this study.
Contact information: Francois-Clement Bidard, Institut Curie, Paris, France.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-10.