RAD001 and Erlotinib in Patients With Neuroendocrine Tumors
The purpose of this study is to test how safe and effective the combination of RAD001 and erlotinib is in patients with neuroendocrine tumors.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase II Study to Evaluate the Safety and Efficacy of RAD001 Plus Erlotinib in Patients With Well- to Moderately-Differentiated Neuroendocrine Tumors|
- To determine the efficacy of RAD001 plus erlotinib in patients with progressive moderately- to well-differentiated NETs as measured by radiographic response rate. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
- To determine the safety of RAD001 plus erlotinib in patients with progressive moderately- to well-differentiated NETs. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
- To determine overall survival. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
- To determine 6-month progression free survival (PFS). [ Time Frame: 3 years ] [ Designated as safety issue: No ]
- To determine time to treatment failure. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
- To determine time to progression. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
- To determine biochemical marker response rate by measuring chromogranin A levels (and other markers as indicated). [ Time Frame: 3 years ] [ Designated as safety issue: No ]
- To analyze the baseline expression of potential biomarkers of mTOR pathway activity: PTEN, pAKT, p70S6K1, pEGFR, p-IRS, p-mTOR, and p-4E-BP. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
- To assess ras mutational status. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
|Study Start Date:||June 2009|
|Estimated Study Completion Date:||January 2015|
|Primary Completion Date:||July 2013 (Final data collection date for primary outcome measure)|
|Experimental: RAD001 and erlotinib||
5 mg/day PO (oral)
Other Name: everolimusDrug: erlotinib
100 mg/day (oral)
Other Name: Tarceva
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).
|United States, California|
|UCSF Helen Diller Family Comprehensive Cancer Center|
|San Francisco, California, United States, 94115|
|Principal Investigator:||Emily K. Bergsland, MD||University of California, San Francisco|