A Phase I open label/ Phase II randomized, double-blind, multicenter study investigating the combination of RAD001 and sorafenib (Nexavar®) in patients with advanced hepatocellular carcinoma

Hepatocellular Carcinoma (HCC) is the 5th most common solid tumor worldwide.
Overall mortality from HCC is high with almost 600,000 deaths worldwide in 2002.
Although various chemotherapy regimens are available based on doxorubicin,
cisplatin or fluorouracil, traditionally, chemotherapy is not considered an
effective treatment scheme for HCC as these tumor are chemoresistent:
chemotherapy response rates of 10% can be seen with single agents and up to
20% response rates with combination based regimens.
The medical need is high for better systemic therapy for advanced HCC and the
limited efficacy of the currently available drug therapies in this population
despite the approval of sorafenib (received registration in the European Union
for the treatment of HCC in 2007)
Mechanism of action of RAD001: the mTOR pathway has been reported to be
activated in 15% to 41% of the cases and mTOR inhibitors (RAD001) show
antineoplastic activity in HCC models. A combination therapy of RAD001 with
sorafenibwhich will target both primary and secondary pathways may be more
effective in enhancing cytotoxicity or cytostatic activity, overcoming possible
resistance and limiting toxicity.

Phase I
- To characterize the safety and tolerability and determine the maximum
tolerated dose of daily RAD001 in combination with daily sorafenib
Phase II
- To estimate the hazard ratio of the treatment effect as measure of anti-tumor
activity of the combination therapy at the maximum tolerated dose-level, as
compared to sorafenib alone
Secundary
Phase I
- To describe any responses: CR, PR, SD, PFS, TTP, time to response, duration
of response
- To characterize the pharmacokinetic (PK) profiles
Phase II
- To describe the clinical efficacy of all study treatments at 24 weeks in
terms of : objective response rate (ORR); disease control rate (DCR);
progression-free survival (PFS)
- To assess the safety and tolerability of RAD001 when combined with sorafenib
as measured by rate and severity of adverse events
- To characterize the PK profile of RAD001 when combined with sorafenib
- To evaluate the drug-drug interaction between RAD001 and sorafenib
Plus numerous exploratory objectives

This is a combined Phase I and Phase II study and each Phase has a Core and an
Extension part of the study. The Core Phase for both Phase I & Phase II
consists of 24 weeks of treatment.
* Phase I Core
Phase I is an open-label, non-randomized, multi-center, designed as a
sequential dose-escalation study combining daily RAD001 plus daily sorafenib,
after which phase II will be initiated in sequence
* Phase II Core
Phase II is a randomized, double-blind, parallel, two-arm multi-center study.
Randomisation over treatment arms:
1. Sorafenib 400 mg BID + RAD001 (at the phase 1 MTD dose-level)
2. Sorafenib 400 mg BID + placebo to RAD001

Once assigned to one of the 2 treatment arms the patient will be assigned,
within that arm, to one of the 2 drug run-ins:
* 8 day run-in with sorafenib 400 mg BID then sorafenib 400 mg BID +
RAD001/placebo
* 8 day run-in with RAD001/placebo then sorafenib 400 mg BID + RAD001/placebo
Randomized in a 1:1 ratio for a total of 40 patients per treatment arm.
* Extension part of Phase I and Phase II
Following completion of 24 weeks of treatment or early discontinuation all
patients may continue to receive RAD001 along with sorafenib or alone, until
progressive disease or unacceptable toxicity occurs.

treatment with Sorafenib 400 mg BID + RAD001 (at the phase I MTD dose-level) or
Sorafenib 400 mg BID + placebo. Phase I starting dose for dose finding is
RAD001 2.5 mg p.o. daily.

- every potential side effect of RAD001 and/or Sorafenib
- Physical examinations including vital signs, standard MRI / CT scans, ECG,
blood for PK assessment, regular monitoring of hematology (including
coagulation parameters), blood chemistry, serum/urine pregnancy, blood
biomarkers, and urinalyses