Fase I/II study: RAD001 and sorafenib combination in patients with advanced hcc.

Design:
Combined Phase I (open-label, designed as a sequential dose-escalation study combining daily RAD001 plus daily sorafenib)and Phase II (randomized, double-blind) trial



Subjects:
patients with advanced hepatocellular carcinoma.



Study medication:
Sorafenib 400 mg BID + RAD001 (at the phase 1 MTD dose-level)



Clinical Phase:
Combined phase I and phase II



Objectives:
Phase 1: Evaluate the safety and tolerability of RAD001 in combination with sorafenib in patients with advance hepatocellular cancer (HCC) and to determine the maximum tolerated dose (MTD).
Phase 2: To estimate the treatment effect as a measure of anti-tumor activity in terms of Time to Progression (TTP) of the combination of RAD001 plus sorafenib, at the MTD, as compared to sorafenib alone.



Primary efficacy variable:

1. Phase I: Dose Limiting Toxicities (DLT) of treatment combination of RAD001 plus sorafenib;

A. Pharmacokinetic measures of systemic exposure, such as AUC, Cmax and trough blood levels.

2. Both Phase I and II: efficacy evaluation based on the overall response rate according to RECIST.



Secondary efficacy variables:

1. Clinical efficacy in terms of: objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), according to RECIST.

2. Safety and tolerability: rate and severity of adverse events.

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 will be cohort driven with evaluation timepoints after 28 days of treatment.
In phase II evaluation will be eventdriven. (time to progression).

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 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.