A Phase II Study to Evaluate the Safety and Efficacy of RAD001 Plus Erlotinib in Patients With Well- to Moderately-Differentiated Neuroendocrine Tumors
Preclinical data suggest that concomitant inhibition of two non-redundant amplified pathways
(mTOR and EGFR) can reverse drug resistance and more profoundly affect tumor growth than
targeting either pathway alone. EGFR inhibitors may abrogate feedback loops that stimulate
upstream signaling events such as PI3K and Akt in the face of mTOR inhibition. Although ErbB
receptors signal through mTOR-dependent mechanisms, mTOR-independent ErbB receptor signaling
also occurs in cancer. Furthermore, deregulation of apoptotic pathways like the
PI3K/Akt/PTEN axis (e.g. via PTEN loss of function or AKT gene amplification) may lead to
resistance to EGFR inhibitors. Treatment with an inhibitor of mTOR may reverse this
resistance. Targeting the mTOR and EGFR pathways concurrently may more effectively inhibit
tumor growth than inhibiting either pathway alone.
The compelling preclinical data, coupled with modest single agent activity seen with EGFR
inhibition and mTOR inhibition in NETs, provides a strong rationale for studying the
activity of concomitant pathway inhibition in patients with advanced NETs. Support for this
strategy also stems from the fact that EGFR inhibitors can be safety combined with mTOR
inhibitors in humans. Emerging data from a phase I study of RAD001 plus erlotinib in
patients with previously treated advanced non-small cell lung cancer (NSCLC) suggests that
the two agents can be safely combined at the following doses: RAD001 5 mg PO q D and
erlotinib 150 mg PO qD.
Of note, the original dose selections for RAD001 and erlotinib for this study stem directly
from phase I studies with this combination (RAD001 5 mg PO qD plus erlotinib 150 mg PO qD).
The modified dose selections (RAD001 5 mg PO qD plus erlotinib 100 mg PO qD) are the result
of integrating discussions with the study sponsor, preliminary safety data from the first
few patients enrolled in this study (suggesting that some patients tolerate full-dose
therapy and others do not) and additional phase I data suggesting that the MTD in some
patient populations is lower than in others, e.g. the MTD in breast cancer patients is
RAD001 2.5 mg PO qD and erlotinib 100 mg PO QD (Mayer et al. ASCO 2009 Breast Cancer
Symposium, Abstract #254).
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the efficacy of RAD001 plus erlotinib in patients with progressive moderately- to well-differentiated NETs as measured by radiographic response rate.
Emily K. Bergsland, MD
University of California, San Francisco
United States: Food and Drug Administration
|UCSF Helen Diller Family Comprehensive Cancer Center||San Francisco, California 94115|