457P - A phase I dose escalation and expansion trial of BKM120, an oral pan-PI3K inhibitor, in patients with advanced solid tumors: analysis of pharmacodyn...

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Drug Development
Presenter Jordi Rodon
Authors J. Rodon1, J. Bendell2, A.R.A. Razak3, M. de Jonge4, F. Eskens5, E. Di Tomaso6, D. Sternberg7, L. Wang8, C. Sarr9, J. Baselga10
  • 1Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 2Drug Development Unit, Sarah Cannon Research Institute, 37203 - Nashville/US
  • 3Dept. Of Medical Oncology And Hematology, Princess Margaret Hospital, M5G 2M9 - Toronto/CA
  • 4Department Of Medical Oncology, Erasmus University Medical Center, Rotterdam/NL
  • 5Dept. Of Medical Oncology, Erasmus University Medical Center, NL-3015 CE - Rotterdam/NL
  • 6Institutes For Biomedical Research, Novartis, MA - Cambridge/US
  • 7Oncology, Novartis Oncology, Florham Park/US
  • 8Oncology Bdm, Novartis Institutes for Biomedical Research, Cambridge/US
  • 9Modeling & Simulation, Novartis Pharmaceuticals, 07936-1080 - East Hanover/US
  • 10Hematology/oncology, MGH Cancer Center, Massachusetts General Hospital, MA 02114 - Boston/US



The MTD of single-agent BKM120 was previously declared as 100 mg/day in a Phase I study in patients (pts) with advanced solid tumors (NCT01068483; Bendell et al. 2011). Here we report on the analysis of pharmacodynamic biomarkers from pts in the dose-escalation and dose-expansion arms of the Phase I study. The inhibitory effects of BKM120 were investigated (i) in the context of glucose metabolism regulation, a known PI3K-dependent process, and (ii) in the context of tumor biology, by surveying the phosphorylation of proteins downstream of PI3K.


83 pts received oral daily BKM120. Tumor samples were analyzed for PIK3CA mutation and PTEN expression. Blood C-peptide (glucose metabolism) was measured at Cmax (2–4 hrs post-dose) on Day 1 in 72 pts. Pathway phosphorylation in surrogate tissue was investigated in 51 paired skin samples by correlating changes in pS6 (baseline to Day 28) with the mean dose of BKM120 administered in each pt. In 8 pts where pre/post treatment biopsies could be obtained, pS6, pAKT, p4EBP1 and Ki67 were quantified within limits of tissue availability.


Blood C-peptide at Cmax on Day 1 increased as a function of the 1st dose administered, with no change after 12.5 mg and mean increase of 72% (range: 56–84%) after 150 mg. Inhibition of pS6 on Day 28 (range: 20–60%) was observed in tumor tissue from 5 out of 8 pts. 4 of these 5 pts also demonstrated a decrease in either pAKT (range: 30–70%) or p4EBP1 (range: 27–35%) with 1 pt displaying a mean 30% decrease in all 3 markers. A decrease in proliferation as measured by Ki67 was observed in 4 pts (range: 13–60%) suggesting a potential biological impact in response to PI3K pathway inhibition. Inhibition of pS6 in skin increased moderately with the mean administered dose of BKM120 (mean inhibition of –28, –37, and –40%, for 12.5–60 mg, >60–90 mg, and >90 mg dose ranges, respectively) suggesting a relationship between treatment dose and the degree of PI3K pathway inhibition.


This analysis supports the notion that daily BKM120 not only has the ability to induce inhibition of the immediate effector of PI3K (pAKT) but also to downregulate the pathway further downstream (pS6) at MTD.


F. Eskens: Membership on an advisory board: Participant of LEAD summit meetings (Novartis).

E. Di Tomaso: Employee of Novartis.

D.W. Sternberg: Employee of Novartis.

L. Wang: Employee of Novartis.

C. Sarr: Employee of Novartis. Stock Ownership in Novartis Pharmaceuticals.

J. Baselga: Novartis Scientific Ad Board (NVPBKM120); other pan‐PI3K inhibitors: Consulting for Exelixis; XL147; Roche‐Genentech Scientific Ad Board; GDC0941. All consulting relationships have CA's in place which conform to the Partners/Harvard COI Policies.

All other authors have declared no conflicts of interest.