A Safety Study of LBH589 (Panobinostat) and RAD001 (Everolimus) to Stabilize Kidney Cancer

The tyrosine kinase inhibitors sunitinib and sorafenib which target the VEGF pathway are now
standard of care for renal cell carcinoma patients and are used as first-line agents.

mTOR inhibitors which have been shown to have direct antitumor effects against renal cell
carcinoma cells and also decrease angiogenesis by downregulation of HIF-1ά are another
promising class of agents in renal cell carcinoma. Recently, the mTOR inhibitor temsirolimus
was approved as a first-line agent for metastatic renal cell carcinoma in patients with
decreased performance status. An improvement in overall-survival was seen when compared to
the interferon alpha treatment group.

We have recently shown in preclinical studies that HDAC inhibitors induce HIF-1ά inhibition
by increased acetylation and polyubiquitination and subsequently increased degradation.
Furthermore, in preclinical models we have demonstrated the in vivo and in vivo
antiangiogenic activity for the single agent LBH589.

Based on these data, we hypothesized that the combination of a HDAC inhibitor and an mTOR
inhibitor may have greater antiangiogenic and antitumor activity than single agents in a
renal cell carcinoma model.

Taken together, these data suggests that the antiangiogenic activity of the HDAC inhibitor
LBH589 and its direct antitumor effect may increase the therapeutic effect of RAD001,
further delay disease progression and increase progression-free survival in patients with
metastatic renal cell carcinoma (RCC). With this clinical trial, we will test for the
efficacy of this particular combination as second line treatment in patients with metastatic
renal cell carcinoma progressing after prior cytokine and /or tyrosine kinase inhibitor
treatment.

This is a dose escalation study. The Phase II dose will be based upon Phase I findings.
Patients will be allowed to remain on therapy provided that they are tolerating therapy and
do not develop progressive disease.