PMID- 29948356 OWN - NLM STAT- MEDLINE DCOM- 20200121 LR - 20200306 IS - 1573-0646 (Electronic) IS - 0167-6997 (Linking) VI - 37 IP - 1 DP - 2019 Feb TI - A phase Ib study of sonidegib (LDE225), an oral small molecule inhibitor of smoothened or Hedgehog pathway, in combination with docetaxel in triple negative advanced breast cancer patients: GEICAM/2012-12 (EDALINE) study. PG - 98-108 LID - 10.1007/s10637-018-0614-9 [doi] AB - Up-regulation of the Hedgehog (Hh) pathway is implicated in the genesis of a wide range of tumors including triple negative breast cancer (TNBC). Sonidegib is a potent and selective oral inhibitor of Smo, a key component of the Hh signaling pathway. We designed a phase I clinical study to explore the combination of sonidegib plus docetaxel (fixed dose at 75 mg/m(2)) in advanced TNBC patients. The primary objective was to ascertain the combination's maximum tolerated dose and the recommended phase II dose (RP2D), based on dose limiting toxicities (DLTs) in the first 2 cycles. A standard "3 + 3" design was followed including three dose levels (DL) of sonidegib: 400 mg (DL1), 600 mg (DL2), and 800 mg (DL3). Twelve patients were included. Sonidegib 800 mg orally q.d. plus docetaxel 75 mg/m(2) given intravenously on day 1 of 21-day cycles was established as the RP2D. No DLTs were observed at any DL. The median number of administered cycles at DL3 was 8 (range: 6 to 9). Grade 3 adverse events (AEs) at DL3 were neutropenia (66.7%), CPK increase (33.3%), leukopenia (33.3%), and paresthesia (33.3%), grade 4 AEs were not reported at this DL. At the RP2D, the combination showed antitumor activity in three out of 10 patients with measurable disease. Median time to progression for the overall study was 42.5 days (95% Confidence Interval: 29-155), and 188 days at DL3. No drug-to-drug interactions between sonidegib and docetaxel were found in the PK assessment. Trial Registration: EudraCT study number: 2013-001750-96. Study GEICAM/2012-12. TRIAL REGISTRATION: EudraCT study number: 2013-001750-96. Study GEICAM/2012-12. ClinicalTrials.gov: NCT02027376. FAU - Ruiz-Borrego, Manuel AU - Ruiz-Borrego M AD - Department of Medical Oncology, Hospital Universitario Virgen del Rocio, Sevilla, Spain. FAU - Jimenez, Begona AU - Jimenez B AD - Department of Medical Oncology, Hospital Clinico Universitario Virgen de la Victoria, IBIMA, Malaga, Spain. FAU - Antolin, Silvia AU - Antolin S AD - Department of Medical Oncology, Complejo Hospitalario Universitario A Coruna, A Coruna, Spain. FAU - Garcia-Saenz, Jose A AU - Garcia-Saenz JA AD - Department of Medical Oncology, IdISSC, CIBERONC-ISCIII, Hospital Clinico San Carlos, Madrid, Spain. FAU - Corral, Jesus AU - Corral J AD - Department of Medical Oncology, Hospital Universitario Virgen del Rocio, Sevilla, Spain. FAU - Jerez, Yolanda AU - Jerez Y AD - Department of Medical Oncology, Instituto de Investigacion Sanitaria Gregorio Maranon, Madrid, Spain. FAU - Trigo, Jose AU - Trigo J AD - Department of Medical Oncology, Hospital Clinico Universitario Virgen de la Victoria, IBIMA, Malaga, Spain. FAU - Urruticoechea, Ander AU - Urruticoechea A AD - Department of Medical Oncology, Fundacion Onkologikoa, San Sebastian, Spain. FAU - Colom, Helena AU - Colom H AD - Department of Biopharmaceutics and Pharmacokinetics, School of Pharmacy, University of Barcelona, Barcelona, Spain. FAU - Gonzalo, Nuria AU - Gonzalo N AD - Department of Pharmacy, IDIBELL, Catalan Institute of Oncology, Hospital Duran i Reynals, L'Hospitalet de Llobregat, Barcelona, Spain. FAU - Munoz, Carmen AU - Munoz C AD - Department of Pharmacy, IDIBELL, Catalan Institute of Oncology, Hospital Duran i Reynals, L'Hospitalet de Llobregat, Barcelona, Spain. FAU - Benito, Sara AU - Benito S AD - GEICAM, Spanish Breast Cancer Group, San Sebastian de los Reyes, Madrid, Spain. FAU - Caballero, Rosalia AU - Caballero R AD - GEICAM, Spanish Breast Cancer Group, San Sebastian de los Reyes, Madrid, Spain. FAU - Bezares, Susana AU - Bezares S AD - GEICAM, Spanish Breast Cancer Group, San Sebastian de los Reyes, Madrid, Spain. FAU - Carrasco, Eva AU - Carrasco E AD - GEICAM, Spanish Breast Cancer Group, San Sebastian de los Reyes, Madrid, Spain. FAU - Rojo, Federico AU - Rojo F AD - Department of Pathology, Instituto de Investigacion Sanitaria Fundacion Jimenez Diaz, Centro de Investigacion Biomedica en Red de Oncologia, CIBERONC-ISCIII, Madrid, Spain. FAU - Martin, Miguel AU - Martin M AUID- ORCID: 0000-0001-9237-3231 AD - Department of Medical Oncology, Instituto de Investigacion Sanitaria Gregorio Maranon, Universidad Complutense, Centro de Investigacion Biomedica en Red de Oncologia, CIBERONC-ISCIII, C/Dr. Esquerdo 46, 28009, Madrid, Spain. mmartin@geicam.org. LA - eng SI - ClinicalTrials.gov/NCT02027376 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20180609 PL - United States TA - Invest New Drugs JT - Investigational new drugs JID - 8309330 RN - 0 (Biphenyl Compounds) RN - 0 (Pyridines) RN - 0 (SMO protein, human) RN - 0 (Smoothened Receptor) RN - 0RLU3VTK5M (sonidegib) RN - 15H5577CQD (Docetaxel) SB - IM MH - Adult MH - Aged MH - Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics/*therapeutic use MH - Biphenyl Compounds/administration & dosage MH - Carcinoma, Ductal, Breast/*drug therapy/metabolism/pathology MH - Docetaxel/administration & dosage MH - Female MH - Humans MH - Maximum Tolerated Dose MH - Middle Aged MH - Prognosis MH - Pyridines/administration & dosage MH - Smoothened Receptor/*antagonists & inhibitors MH - Tissue Distribution MH - Triple Negative Breast Neoplasms/*drug therapy/metabolism/pathology OTO - NOTNLM OT - Hedgehog OT - Triple negative OT - advanced breast cancer OT - docetaxel OT - hormone receptor and HER2 negative OT - sonidegib EDAT- 2018/06/28 06:00 MHDA- 2020/01/22 06:00 CRDT- 2018/06/28 06:00 PHST- 2018/04/05 00:00 [received] PHST- 2018/05/24 00:00 [accepted] PHST- 2018/06/28 06:00 [pubmed] PHST- 2020/01/22 06:00 [medline] PHST- 2018/06/28 06:00 [entrez] AID - 10.1007/s10637-018-0614-9 [pii] AID - 10.1007/s10637-018-0614-9 [doi] PST - ppublish SO - Invest New Drugs. 2019 Feb;37(1):98-108. doi: 10.1007/s10637-018-0614-9. Epub 2018 Jun 9.