An open-label, multicenter phase II study to compare the efficacy and safety of RAD001 as first-line followed by second-line sunitinib versus sunitinib as first-line followed by second-line RAD001 in the treatment of patients with metastatic renal cell carcinoma

The past 5 years have seen a dramatic expansion of therapeutic options in the
treatment of metastatic renal cell carcinoma. The introduction of VEGF targeted
therapies such as sorafenib, sunitinib, bevacizumab and mTOR inhibitors
temsirolimus and everolimus have completely changed the treatment paradigm.
Despite this progress, metastatic RCC still remains a fatal disease and the
development of new treatments are needed to help improve the outcome for these
patients.

RAD001 (everolimus, Afinitor®) is an oral mTOR inhibitor. It targets mTOR, a
key protein kinase in regulating cell growth, proliferation and survival. The
anticancer activity has recently been confirmed in a phase 3 study. In this
study RAD001 significantly prolonged the progression-free-survival compared to
placebo (median PFS of 4,9 vs. 1,87 months) in patients with mRCC which had
progressed on sunitinib, sorafenib or both.

Sunitinib is an oral multi-kinase inhibitor targeting several receptor tyrosine
kinases (PDGFR-*, VEGFR2, c-KIT). In a phase 3 study, sunitinib significantly
prolonged progression-free-survival compared to IFN-* in mRCC patients who had
not received previous systemic therapy (median PFS of 11 vs. 5 months).

RAD001 and temsirolimus have both been combined with sunitinib in phase I
trials, but due to toxicity concomitant use of these agents is not recommended.

RAD001 and sunitinib have been studied in phase 2 trials as single agents for
mRCC patients who had previously received cytokines therapies. The PFS reported
was prolonged relative to historical controls.

Therefore, the rationale for sequencing RAD001 and sunitinib is warranted to
investigate the efficacy and safety of both agents as first-line and
second-line treatment in mRCC and to evaluate the feasibility of a phase III
study with RAD001 to demonstrate significant improvement as a first-line
treatment over sunitinib in patients with mRCC.

To evaluate the probability that the progression free survival (PFS) in the
first-line treatment with RAD001 is non-inferior to the first-line treatment
with sunitinib for patients with metastatic renal cell carcinoma (primary
objective). Additionally, the purpose is to compare the PFS combined after the
second-line and to evaluate the safety profile of RAD001 and sunitinib in both
the first-line and second-line therapy setting.

In a phase II, open-label, multi-centre, international, non-inferiority trial
patients will be randomized to receive either 10 mg RAD001 p.o (continuous)
followed by sunitinib 50 mg p.o. (4 weeks on/2 weeks off) or vice versa.
Patients will be stratified according to the Memorial Sloan Kettering Cancer
Center (MSKCC) Risk Criteria.

Treatment with RAD001 and sunitinib should be continued as long as the patient
is not progressing and tolerates the study treatment.

Patients will be eligible to cross over to the second-line medication and will
stop second-line medication in case of documented disease progression or in
case of discontinuation due to unacceptable toxicity or for other reasons (for
example withdrawal of consent).

Patients will be instructed to use RAD001 10 mg daily oral dose or sunitinib 50
mg oral dose 4 weeks on/2 weeks off. The duration of 1 cycle is 42 days.

After the screeningsperiod patients have to visit the hospital every 1st and
28th day of each treatment cycle (1st and 2nd line) which consists of 42 days.
Tumor evaluations will be performed before the start of first-line study
medication and every 12 weeks during both 1st and 2nd line treatment, until
progression of disease. When discontinued for reasons other than disease
progression, tumor evaluations have to be continued until disease progression
or until initiation of another anti-cancer therapy.
Before cross-over to the second-line of medication, patients have to repeat the
specified baseline assessments. Baseline tumor evaluations for the second-line
period will only be necessary if the time between the last tumor evaluation
(which lead to documentation of disease progression in 1st line) and start of
2nd line treatment is greater than 35 days.
After completion or discontinuations of both lines of study medication, all
patients will return for an end-of treatment visit.
Patients who permanently discontinue with the study will have a safety
follow-up visit 28 days after the last dose of medication and they will be
followed for survival after 28 days and thereafter each 2 months for up to 3
years after the last patient is randomized to the study.
Use of RAD001 might cause side effects.