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A Phase II Study to Evaluate the Safety and Efficacy of RAD001 Plus Erlotinib in Patients With Well- to Moderately-Differentiated Neuroendocrine Tumors

Phase 2
18 Years
Open (Enrolling)
Neuroendocrine Tumors

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Trial Information

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).

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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the efficacy of RAD001 plus erlotinib in patients with progressive moderately- to well-differentiated NETs as measured by radiographic response rate.

Outcome Time Frame:

3 years

Safety Issue:


Principal Investigator

Emily K. Bergsland, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of California, San Francisco


United States: Food and Drug Administration

Study ID:




Start Date:

June 2009

Completion Date:

March 2013

Related Keywords:

  • Neuroendocrine Tumors
  • neuroendocrine
  • islet cell
  • carcinoid
  • pancreatic neuroendocrine
  • paraganglioma
  • pheochromocytoma
  • RAD001
  • everolimus
  • erlotinib
  • Tarceva
  • Neuroendocrine Tumors



UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California  94115