RAD001 and Erlotinib in Patients With Neuroendocrine Tumors
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|ClinicalTrials.gov Identifier: NCT00843531|
Recruitment Status : Terminated (Low Accrual)
First Posted : February 13, 2009
Results First Posted : September 29, 2020
Last Update Posted : September 29, 2020
|Condition or disease||Intervention/treatment||Phase|
|Neuroendocrine Tumors||Drug: RAD001 Drug: erlotinib||Phase 2|
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 neuroendocrine tumors (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 maximum tolerated dose (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. American Society of Clinical Oncology (ASCO) 2009 Breast Cancer Symposium, Abstract #254).
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||17 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
|Actual Study Start Date :||June 25, 2009|
|Actual Primary Completion Date :||July 16, 2013|
|Actual Study Completion Date :||August 20, 2016|
Experimental: RAD001 and erlotinib
Each 28 day cycle:
RAD001: 5 mg per day by mouth (self-administered) Erlotinib: 100 mg per day by mouth (self-administered)
5 mg/day PO (oral)
Other Name: Everolimus
100 mg/day (oral)
Other Name: Tarceva
- Objective Response Rate (ORR) [ Time Frame: Up to 2 years ]Objective response is defined as complete response (CR) or partial response (PR) assessed using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The primary analysis population is based on efficacy-evaluable patients, defined as those patients who receive at least one cycle of RAD001 plus erlotinib and undergo at least one post-baseline response assessment or die while on therapy.
- Number of Patients With Dose-limiting Toxicity (DLT) [ Time Frame: Up to 9 months ]Primary safety analysis will be conducted after the first 16 patients have had potential for completion of two cycles of protocol therapy. All patients receiving at least one dose of protocol therapy will be included in the analyses. All patients with treatment-related, Grade 3 or higher adverse events according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3 resulting in a DLT will be reported.
- Duration of Objective Response [ Time Frame: Up to 2 years ]Duration of objective response will be defined as the time from the initial documentation of response to documented disease progression or death from any cause on study
- Overall Survival [ Time Frame: Up to 3 years ]Overall survival will be defined as the time from first day of treatment until death
- Median Progression-Free Survival (PFS) [ Time Frame: Up to 3 years ]PFS will be defined as the time from the first day of treatment and documented objective response to time of progression or death from any cause, whichever occurs first
- Time to Progression [ Time Frame: Up to 3 years ]Time to disease progression will be defined as the time from baseline until documented disease progression or death (whichever occurs first).
- Time to Treatment Failure (TTF) [ Time Frame: Up to 3 years ]Time to treatment failure will be defined as the time from first day of treatment until study discontinuation (for any cause).
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00843531
|United States, California|
|University of California, San Francisco|
|San Francisco, California, United States, 94115|
|Principal Investigator:||Emily K. Bergsland, MD||University of California, San Francisco|