Abstract OT3-01-02: A phase I-II trial of dasatinib in combination with trastuzumab (T) and paclitaxel in the first line treatment of HER2 positive metastatic breast cancer (MBC) patients: GEICAM/2010-04
Authors: Ocaña A , Ruiz Borrego M , Gil-Martín M , Antolín S , Guerrero Á , Vidal Boixader L , Martín M , Trigo Pérez JM , Rojo F , Jerez Y , Atienza M , Pernas S , Hernando A , Carrasco E , Benito S , Caballero R , Pandiella A 
Published: May 2016

Abstract
Background: Resistance to targeted-therapies is a current problem in our clinical practice. In HER2 overexpressing tumors, resistance to trastuzumab-based therapies is widely observed. Expression of SRC has been pre-clinically linked to trastuzumab resistance and the addition of the multi-tyrosine kinase inhibitor dasatinib to trastuzumab increases its antitumor activity (Seoane S, et al. J Natl Cancer Inst. 2010). On previous studies, Dasatinib showed a good toxicity profile, with low grade 3-4 toxicity rates (E. Mayer, et al. J Clin Oncol 2009). We have designed a phase I-II trial combining dasatinib with standard trastuzumab/paclitaxel. (ClinicalTrials.gov Identifier: NCT01306942). In this abstract we report the description of the phase II part of the trial which is ongoing.
Trial Design: Eligible patients must be HER2+ (evaluated by central laboratory and assessed by immunohistochemistry and fluorescent in-situ hybridization) MBC and candidates for trastuzumab + chemotherapy as first line treatment. Taxanes and trastuzumab administered in the adjuvant setting are permitted if given &gt;12 months before the inclusion. Patients with CNS involvement are eligible if treated and clinically stable without medication. Treatment consists of trastuzumab 2 mg/kg weekly (following a loading dose of 4 mg/kg in cycle 1), weekly paclitaxel (80 mg/m2, 3 weeks on-one week off) and dasatinib 100 mg once daily (based on the recommended phase II dose from the phase I part, Gil-Martin M, et al. European Breast Cancer Conference 2014, P-041) in a 28-days cycle. Patients are treated until radiologic or symptomatic progression or unacceptable toxicity.
The primary objective for this phase II is efficacy, measured by Objective Response Rate (ORR according to RECIST 1.1). Secondary objectives are: Safety (evaluated using NCI-CTCAE v 4.03), Clinical Benefit Rate, Time to Progression, Progression Free Survival and Response Duration. Pharmacodynamic biomarkers include pAKT, pS6, pSRC, pErk1/2 in tumor tissue samples, mononuclear cells in blood samples and in skin tissue. An additional exploratory objective is to evaluate the correlation between the early presence of lymphocytosis and efficacy. The study will be considered positive if ORR increases 25% from a 50% ORR observed in previous studies with paclitaxel + trastuzumab. We need to include 28 evaluable patients to demonstrate this hypothesis (with an alpha error of 0.05 and a statistical power of 80%), assuming a 10% drop-out rate. Twenty one patients have already been included. Recruitment is expected to finish by the end of 2015.
Citation Format: Ocaña A, Ruiz Borrego M, Gil-Martín M, Antolín S, Guerrero Á, Vidal Boixader L, Martín M, Trigo Pérez JM, Rojo F, Jerez Y, Atienza M, Pernas S, Hernando A, Carrasco E, Benito S, Caballero R, Pandiella A. A phase I-II trial of dasatinib in combination with trastuzumab (T) and paclitaxel in the first line treatment of HER2 positive metastatic breast cancer (MBC) patients: GEICAM/2010-04. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-02.