An open label, stratified, single-arm phase II study of RAD001 in patients with advanced pancreatic neuroendocrine tumor (NET) after failure of cytotoxic chemotherapy

RAD001 has been evaluated in phase 1 studies involving 147 patients with
advanced cancers using both a weekly regimen (up to 70mg/wk) and a daily
regimen (10mg/d). The adverse events are mild-moderate (CTC grade 1-2) in the
majority of patients.

The dose and schedule of 10mg p.o. q.d has been selected for most phase 2
studies based on assessment of both pharmacodynamic and safety studies.
Conventional cytotoxic agents were empirically evaluated in in vitro and in
vivo pharmacology studies as combination partners for RAD001 and have shown
that RAD001 is additive or synergistic in combination with other anticancer
agents, including cytotoxics and other signal transduction inhibitors (STIs) as
well as endocrine therapy. In many cases, a potentiation of cell death by the
drug combination was observed.

In pancreatic NET cells, mTOR is activated in response to signaling by
insulin-like growth factor 1 (IGF-1). Interruption of this signaling pathway
through treatment with RAD001 in combination with a somatostatin analogue was
the goal of a recent phase 2 clinical trial conducted by J. Yao at the MD
Anderson Cancer
Center. Of the thirty treated patients, twenty-seven patients were evaluable
for response. Four patients were reported to have partial response, 17 with
stable disease (SD), and 3 with progressive disease (PD) per RECIST. Responses
appeared to be durable.

To determine the objective response rate (ORR) (complete response and partial
response) of RAD001 10 mg po qd monotherapy in patients with advanced
(unresectable or metastatic) pancreatic NET after the failure of cytotoxic
chemotherapy.

This is a stratified two-stage, single-arm, phase 2 study of treatment with
RAD001 in patients with advanced (unresectable or metastatic) pancreatic
neuroendocrine
tumor (NET) after failure of cytotoxic chemotherapy.

Patients are stratified according to whether they are receiving chronic
treatment with Sandostatin LAR® Depot (octreotide acetate for injectable
suspension).
- Stratum 1, consisting of patients not receiving chronic Sandostatin LAR® Depot
therapy, will receive RAD001 monotherapy at 10 mg/day.
- Stratum 2, consisting of patients with tumors that have progressed during
Sandostatin LAR® Depot treatment will continue their entry dose of Sandostatin
LAR® Depot plus RAD001 10 mg/day.

In each of the two strata, a two-stage Simon design is used allowing for early
stopping after stage 1 for lack of activity. If activity is demonstrated after
stage 2,
further patients will be included in a 3rd stage to increase the sample size to
100
patients in stratum 1.

All patients will be treated with RAD001 until tumor progression is documented
per RECIST criteria, until unacceptable toxicity occurs, or until patient or
investigator requests discontinuation of treatment.

In stratum 1 RAD001 will be given at 10 mg po qd by continuous daily dosing
until
tumor progression.

In stratum 2 patients will receive RAD001 10 mg po qd and will continue their
entry
dose of Sandostatin LAR® Depot, both drugs continued until tumor progression.

Toxicity of RAD001 alone or of the combination of RAD001 and Sandostatine LAR.
Radiation exposure of CT-scans.