445O - Dose-escalation study of sonidegib (LDE225) plus buparlisib (BKM120) in patients (pts) with advanced solid tumors

Date 27 September 2014
Event ESMO 2014
Session Developmental therapeutics
Topics Anticancer Agents
Biological Therapy
Presenter QUincy Siu-chung Chu
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors Q.S. Chu1, A. Mahipal2, M. Schuler3, F.G.M. De Braud4, L. Dirix5, A. Rampersad6, J. Zhou7, Y. Wu8, S. Kalambakas6, P.Y. Wen9
  • 1Department Of Oncology, University of Alberta Cross Cancer Institute, T6G 1Z2 - Edmonton/CA
  • 2Clinical Research Unit, H. Lee Moffitt Cancer Center & Research Institute, Tampa/US
  • 3Department Of Medical Oncology, West German Cancer Center, University Hospital Essen, 45122 - Essen/DE
  • 4Medical Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, IT-20133 - Milano/IT
  • 5Clinical Trials Oncology, Oncologisch Centrum Sint-Augustinus, Antwerp/BE
  • 6Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover/US
  • 7Clinical Pharmacology, Novartis Pharmaceuticals Corporation, East Hanover/US
  • 8Biostatistics, Novartis Pharmaceuticals Corporation, East Hanover/US
  • 9Center For Neuro-oncology, Dana-Farber Cancer Insitute, 02215 - Boston/US



Aberrant hedgehog (Hh) signaling has been observed in tumors with dysregulated PI3K signaling. Sonidegib (LDE225; smoothened inhibitor that blocks Hh activity) and buparlisib (BKM120; pan class I PI3K inhibitor) show antitumor activity in ph I studies and combined, enhanced activity in xenograft models. In this ph Ib study (NCT01576666), the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), pharmacokinetic (PK) interaction, and preliminary antitumor activity of LDE225 + BKM120 were assessed in pts with metastatic breast cancer (mBC), pancreatic adenocarcinoma (PANC), metastatic colorectal cancer (mCRC), or recurrent glioblastoma (GBM).


Adult pts received different daily doses (followed by Bayesian logistic regression model) of LDE225 and BKM120, starting at 400 and 60 mg, respectively. Safety, tolerability, PK, antitumor activity, and biomarkers (PIK3CA/PTEN) were assessed. Safety and PK are reported.


Pts (N = 46; 7 mBC, 9 PANC, 19 mCRC, 11 GBM) were enrolled into 5 cohorts (Table). As of Dec 12, 2013, 44 pts (95.7%) discontinued, primarily due to disease progression (n = 29) and adverse events (AEs; n = 7). G 3/4 AEs (> 5%) regardless of study drug included increased alanine and aspartate aminotransferase (21.7% each), increased blood creatine phosphokinase (17.4%), hyperglycemia (8.7%), and increased blood alkaline phosphatase, aphasia, nausea, fatigue (6.5% each). See Table for dose-limiting toxicities (DLTs); MTD was not reached. At the RDE (LDE225 400 mg/BKM120 80 mg), no drug-drug interaction was observed, the interindividual variability of LDE225 and BKM120 PK (cycle 1 D 1) was ≈ 67% and ≈ 30%, respectively, and trough levels over time aligned with single-agent exposure.

Summary of Dose-Limiting Toxicities Observed in the Dose-Escalation Phase

Cohort Dose Level (once daily) DLTs Occurring Within 6 Weeks of First Dose (n = 1 for each) No. of Pts Enrolled No. of Pts With DLTsa/ No. of Evaluable Ptsb
1 LDE225 400 mg + BKM120 60 mg None  6 0/4
2 LDE225 800 mg + BKM120 60 mg - Grade 3 aspartate aminotransferase elevation - Grade 3 anorexia - Grade 3 creatine phosphokinase elevation - Grade 4 creatine phosphokinase elevation  7 2/5
3 LDE225 400 mg + BKM120 80 mg Grade 3 creatine phosphokinase elevation 15 1/7
4 LDE225 400 mg + BKM120 100 mg - Grade 2 photosensitivity - Grade 3 rash - Grade 3 alanine aminotransferase elevation - Grade 3 aspartate aminotransferase elevation  9 3/9
5 LDE225 200 mg + BKM120 100 mg Grade 3 alanine aminotransferase elevation  9 1/4

a Pts w/multiple occurrences of a DLT at 1 dose level were each counted once. b Pts who met the minimum exposure criteria to be included in the dose-determining set.


LDE225 + BKM120 is tolerable, with expected DLTs, consistent with ph I studies. PKs of each agent in combination appear similar to PKs observed in single-agent studies. Based on these data, further study of the combination is warranted.


M. Schuler: participated in advisory boards (compensated) for AstraZeneca, Boehringer Ingelheim (BI), Novartis (NVS), Pfizer; received research funding from BI, NVS; received honoraria for CME lectures from Alexion, BI, Celgene, GSK, Lilly, NVS, Pfizer; A. Rampersad: is employed by Novartis Pharmaceuticals Corporation; J. Zhou: is employed by Novartis Pharmaceuticals Corporation; Y. Wu: is employed by Novartis Pharmaceuticals Corporation and owns stock; S. Kalambakas: is employed by Novartis Pharmaceuticals Corporation and owns stock; P.Y. Wen: participated in an advisory board for Novartis and received research funding from Novartis.All other authors have declared no conflicts of interest.