411TiP - A phase I study of LDE225 in combination with docetaxel in patients with triple negative (TN) advanced breast cancer (ABC): GEICAM/2012-12

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anticancer Agents
Breast Cancer
Biological Therapy
Presenter Miguel Martin Jimenez
Citation Annals of Oncology (2014) 25 (suppl_4): iv116-iv136. 10.1093/annonc/mdu329
Authors M. Martin Jimenez1, M. Ruiz-Borrego2, J.M. Trigo3, S. Antolin4, J.A. Garcia Saenz5, A. Hernando6, A. Ocana7, F. Rojo8, S. López-Tarruella1, L. Paz-Ares9, N. Ribelles10, L. Calvo4, F. Moreno5, R. Caballero11, E. Carrasco12
  • 1Medical Oncology, Instituto Investigación Sanitaria Hospital Gregorio Marañón, 28007 - Madrid/ES
  • 2Medical Oncology, Hospital Universitario Virgen del Rocío, Sevilla/ES
  • 3Medical Oncology, Hospital Universitario Virgen de la Victoria, Malaga/ES
  • 4Medical Oncology, Complejo Hospitalario Universitario A Coruña, A Coruña/ES
  • 5Medical Oncology, Hospital Clínico San Carlos, 28040 - Madrid/ES
  • 6Clinical Operations, GEICAM, San Sebastián De Los Reyes/ES
  • 7Medical Oncology, Complejo Hospitalario Universitario de Albacete, Albacete/ES
  • 8Pathology Department, Fundacion Jimenez Diaz, 28040 - Madrid/ES
  • 9Medical Oncology, Hospital Universitario Virgen del Rocio, 41013 - Sevilla/ES
  • 11Translational Research, GEICAM, San Sebastián De Los Reyes/ES
  • 12Medical, GEICAM, ES-28703 - San Sebastián de los Reyes/ES



LDE225 is a potent and selective oral inhibitor of Smo, a key component of the hedgehog (Hh) signaling pathway. Up-regulation of the Hh pathway is implicated in the genesis of a wide range of tumors including triple negative breast cancer. Here we report an ongoing phase I study exploring the combination of LDE225 with docetaxel in TN ABC patients to identify the Maximum Tolerated Dose (MTD) and the Recommended Phase II Dose (RP2D) (ClinicalTrials.gov Identifier: NCT02027376).

Trial design

Eligibility criteria include patients with TN ABC candidates to receive treatment with docetaxel that have received a maximum of 3 prior chemotherapy regimens. Those patients with CNS involvement are also candidates if treated and clinically stable. Treatment consists of 21-day cycles with docetaxel 75mg/m2 on day 1, every 21 day and LDE225 once daily. We use a standard 3 + 3 design in sequential cohorts (3 dose levels (DL) of LDE225: 400mg once daily (DL1), 600mg once daily (DL2), 800mg once daily (DL3); and a DL-1: LDE225 400mg once daily and docetaxel 60mg/m2 every three weeks). The primary endpoint is the MTD and RP2D of the combination; secondary endpoints include evaluation of safety and tolerability, in addition to pharmacodynamic (PD) and pharmacokinetic (PK) studies. Patients are treated until radiologic or symptomatic progression or unacceptable toxicity occurs. PK will be performed to evaluate whether LDE225 influences the pharmacology of docetaxel. PD assessments include Hg gene expression signature associated to pathway activation in tumor samples and changes in Smo related biomarkers in skin and blood correlative samples. Efficacy will be measured in terms of time to progression and objective response rate. A minimum of 9 and a maximum of 18 patients will be included in this phase I. The study is approved by ERBs and Competent Authority and already recruiting patients (one patient included in DL1).


All authors have declared no conflicts of interest.