RAD001 and Erlotinib in Patients With Neuroendocrine Tumors

Phase 2

Terminated

Conditions: Neuroendocrine Tumors

Interventions: Drug: RAD001
Drug: erlotinib

Registration Number: NCT00843531

Lead Sponsor: University of California, San Francisco

Brief 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.

Detailed 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 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).

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 17

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
Eastern Cooperative Oncology Group (ECOG) ≤2
Absolute Neutrophil Count (ANC) ≥1500/μL
Plts ≥100,000/μL
Hgb >9 gm/dL
Total bilirubin ≤2.0 mg/dL or 1.5X upper limit of normal (ULN)
Serum transaminases ≤2.5x ULN (≤5xULN if liver mets)
Serum Cr ≤2.0 mg/dL or 1.5X ULN
Fasting serum glucose <150 mg/dL or <1.5x ULN
Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤2.5xULN
International Normalized Ratio (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 Diffusing capacity of the lungs for carbon monoxide (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 New York Heart Association (NYHA) Class III or IV
Unstable angina pectoris, symptomatic CHF, myocardial infarction w/in 6 months of Day 1, uncontrolled cardiac arrhythmia or any other significant cardiac disease
Uncontrolled diabetes (fasting serum glucose ≥ 150 mg/dL or >1.5x upper limit of normal (ULN))
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 (patients needing anticoagulation must use low molecular weight heparin (LMWH))
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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
RAD001 and erlotinib	RAD001	Each 28 day cycle: RAD001: 5 mg per day by mouth (self-administered) Erlotinib: 100 mg per day by mouth (self-administered)
RAD001 and erlotinib	erlotinib	Each 28 day cycle: RAD001: 5 mg per day by mouth (self-administered) Erlotinib: 100 mg per day by mouth (self-administered)

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	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.

Secondary Outcome Measures

Name	Time	Method
Duration of Objective Response	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
Number of Patients With Dose-limiting Toxicity (DLT)	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.
Overall Survival	Up to 3 years	Overall survival will be defined as the time from first day of treatment until death
Median Progression-Free Survival (PFS)	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	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)	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).