Overview

This trial is active, not recruiting.

Condition neuroendocrine tumors
Treatments rad001, erlotinib
Phase phase 2
Targets EGFR, mTOR, FKBP-12
Sponsor University of California, San Francisco
Collaborator Genentech, Inc.
Start date June 2009
End date July 2013
Trial size 17 participants
Trial identifier NCT00843531, 084511

Summary

The purpose of this study is to test how safe and effective the combination of RAD001 and erlotinib is in patients with neuroendocrine tumors.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Endpoint classification safety/efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Each 28 day cycle: RAD001: 5 mg per day by mouth (self-administered) Erlotinib: 100 mg per day by mouth (self-administered)
rad001 everolimus
5 mg/day PO (oral)
erlotinib Tarceva
100 mg/day (oral)

Primary Outcomes

Measure
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

Secondary Outcomes

Measure
To determine the safety of RAD001 plus erlotinib in patients with progressive moderately- to well-differentiated NETs.
time frame: 3 years
To determine overall survival.
time frame: 3 years
To determine 6-month progression free survival (PFS).
time frame: 3 years
To determine time to treatment failure.
time frame: 3 years
To determine time to progression.
time frame: 3 years
To determine biochemical marker response rate by measuring chromogranin A levels (and other markers as indicated).
time frame: 3 years
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
To assess ras mutational status.
time frame: 3 years

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion Criteria: - ≥1 measurable disease site per RECIST, not previously irradiated (if previous radiation to marker lesion(s), need evidence of PD) - Histologic dx of well- to moderately-differentiated NET: low- or intermediate-grade, islet cell carcinoma, pancreatic NET, carcinoid, atypical carcinoid, paraganglioma, pheochromocytoma. No longer enrolling carcinoid patients as of 4/25/2011. - ≥4 wks since completion of prior investigational drug tx or other tx(radiation, chemotherapy, immunotherapy, antibody-based tx); recovery from acute toxicities of prior tx - ECOG ≤2 - ANC ≥1500/μL - Plts ≥100,000/μL - Hgb >9 gm/dL - Total bilirubin ≤2.0 mg/dL or 1.5XULN - Serum transaminases ≤2.5xULN (≤5xULN if liver mets) - Serum Cr ≤2.0 mg/dL or 1.5XULN - Fasting serum glucose <150 mg/dL or <1.5xULN - Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤2.5xULN - INR ≤1.5 - Written informed consent, compliance w/study requirements - Archived tissue if available - Negative urine/serum pregnancy test w/in 7 days prior to Day 1 Exclusion Criteria: - Poorly differentiated NET, high-grade NET, adenocarcinoid, goblet cell carcinoid, small cell carcinoma - Major surgery or traumatic injury w/in 4 wks, inadequate recovery from side effects of any surgery, or likely to require major surgery during study - Liver-directed therapy w/in 2 mths of enrollment. Prior tx w/ radiotherapy (including radiolabeled spheres, cyberknife, hepatic arterial embolization (w/ or w/o chemotherapy), cryotherapy/ablation) allowed if areas of measurable disease being used for the study are not affected, or if PD can clearly be documented in the area - Prior tx w/ EGFR inhibitor or mTOR inhibitor - Known hypersensitivity to RAD001 or other rapamycins - Chronic, systemic tx w/ corticosteroids or another immunosuppressive agent (topical or inhaled corticosteroids are allowed) - Immunization w/ attenuated live vaccines w/in 1 wk of study entry or during study - Uncontrolled brain or leptomeningeal mets, including pts who continue to require glucocorticoids for brain or leptomeningeal mets - Other malignancies w/in the past 3 years except for adequately treated carcinoma of the cervix, basal/squamous cell skin carcinomas, or other in situ cancer - Severe and/or uncontrolled intercurrent medical conditions or other conditions that may affect study participation, including, but not limited to: - Severely impaired lung function (spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation ≤88% at rest on room air) - Symptomatic congestive heart failure (CHF) of NYHA Class III or IV - Unstable angina pectoris, symptomatic CHF, myocardial infarction w/in 6 mths of Day 1, uncontrolled cardiac arrhythmia or any other significant cardiac disease - Uncontrolled diabetes (fasting serum glucose ≥ 150 mg/dL or >1.5xULN) - Any active (acute or chronic) or severe infection, disorder, or nonmalignant medical illness that is uncontrolled or whose control may be jeopardized by study tx - Liver disease - Hx of HIV seropositivity or other immunocompromised state - GI function impairment or disease that may alter absorption of RAD001 or erlotinib - Active, bleeding diathesis or on oral anti-vitamin K medication (pts needing anticoagulation must use LMW heparin) - Hx of other disease, metabolic dysfunction, or physical exam or lab finding giving reasonable suspicion of disease/condition that contraindicates study tx, might affect study results or puts the pt at high risk - Pregnant or breast feeding females - Adults of reproductive potential not willing to use effective methods of birth control during tx and ≥8 wks after completing tx - Inability to comply w/ objectives and procedures - Inability to comply w/ concomitant medication restrictions

Additional Information

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
Principal investigator Emily K. Bergsland, MD
Description 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).
Trial information was received from ClinicalTrials.gov and was last updated in May 2015.
Information provided to ClinicalTrials.gov by University of California, San Francisco.