281P - A phase I study of sonidegib (S) in combination with docetaxel (D) in patients (pts) with triple negative (TN) advanced breast cancer (ABC): GEICAM...

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Breast Cancer
Presenter Miguel Martín
Citation Annals of Oncology (2016) 27 (6): 68-99. 10.1093/annonc/mdw365
Authors M. Martín1, M. Ruiz-Borrego2, J.M. Trigo Perez3, S. Antolín4, J.A. García-Sáenz5, J. Corral6, Y. Jerez7, A. Urruticoechea8, H. Colom9, N. Gonzalo10, C. Muñoz10, J. Cuevas2, C. del Monte11, L. Pérez-Ramos12, R. Caro13, A. Blach14, S. Benito11, S. Bezares Montes15, E. Carrasco16, F. Rojo17
  • 1Department Of Medical Oncology, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense de Madrid, 28007 - Madrid/ES
  • 2Dept Of Oncology, Hospital Universitario Virgen del Rocio, Sevilla/ES
  • 3Medical Oncology, Hospital Universitario Virgen de la Victoria, Malaga/ES
  • 4Medical Oncology, Hospital Universitario a Coruna - a Corunac, A Coruna/ES
  • 5Medical Oncology, Hospital Clinico Universitario San Carlos, Madrid/ES
  • 6Medical Oncology, Hospital Universitario Virgen del Rocio, 41013 - Sevilla/ES
  • 7Medical Oncology, Hospital General Universitario Gregorio Marañon, Madrid/ES
  • 8Medical Oncology, Onkologikoa-Kutxaren Instituto Onkologikoa, San Sebastian/ES
  • 9Faculty Of Pharmacy, Universitat de Barcelona, 08028 - Barcelona/ES
  • 10Pharmacinetics Lab, Institut Català d'Oncologia Hospital Duran i Reynals, Barcelona/ES
  • 11Clinical Operations, GEICAM Spanish Breast Cancer Group, Madrid/ES
  • 12Statistics, GEICAM Spanish Breast Cancer Group, Madrid/ES
  • 13Data Management, GEICAM Spanish Breast Cancer Group, Madrid/ES
  • 14Translational Research, GEICAM Spanish Breast Cancer Group, Madrid/ES
  • 15Medical Lead, GEICAM Spanish Breast Cancer Group, Madrid/ES
  • 16GEICAM (Spanish Breast Cancer Research Group), Madrid/ES
  • 17Pathology Department, University Hospital "Fundacion Jimenez Diaz", Madrid/ES



S 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 TN breast cancer. Here we report a phase I study exploring the combination of S with D in TN ABC pts to identify the Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) (ClinicalTrials.gov Identifier: NCT02027376).


Pts with ≤3 prior chemotherapy regimens for ABC were included. Treatment consisted of 21-day cycles (cy) of D 75mg/m2 on day 1, and increasing doses of S given once daily (QD). A standard 3 + 3 design was followed including 3 dose levels (DL) for S: DL1 400mg, DL2 600mg and DL3 800mg. The primary objective was to define the MTD and RP2D of the combination, based on dose-limiting toxicities (DLT) in the first 2 cy; secondary objectives included the evaluation of safety, changes on QTc, efficacy, and pharmacokinetics (PK).


12 pts were included (5 at DL1, 4 at DL2 and 3 at DL3); 3 pts were replaced due to early progressive disease (PD). Median age was 49.5 years (26–76). Pts received a median of 2 cy (2–4) at DL1, 2 cy (1–3) at DL2 and 8 cy (6–9) at DL3. No DLTs were observed in any DL. DL3 was the MTD, and toxicities grade (G) 3, none G4, in all cy included neutropenia (NP) 66.7%, CPK increase, leukopenia, and paresthesia 33.3% each; 1 event of NP and the event of CPK increase caused S dose reduction. 2 pts had G1 QTc prolongation. The mean relative dose intensity of S and D were 99.3% (94.1–100.8) and 100% (98.9-102.4), respectively. 11 pts discontinued study treatment due to PD and 1 pt by Investigator's criterion (on complete response at DL3). The objective response rate (n = 10) was 10% (95% CI 0.3-44.5). Median time to progression (n = 12) was 42.5 days (95% CI 29-155), being of 188 days at DL3. When co-administrated S and D, there was a trend to lower S trough concentrations, but could not be proved to be statistically significant and D clearance was similar on day 1 of Cycles 1 and 2.


S can be safely combined with D. Co-administration of S and D seems not to have PK interaction. S 800mg QD and D 75mg/m2 was declared as the RP2D.

Clinical trial identification

Nº EudraCT: 2013-001750-96

Legal entity responsible for the study

GEICAM (Spanish Breast Cancer Group)


Novartis Farmaceutica S.A.


All authors have declared no conflicts of interest.