Neoplasms

All Conditions

Rare Diseases

Neuroendocrine Tumors

Pheochromocytoma

Paraganglioma

Carcinoid Tumor

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Neuroendocrine Tumor

Paragangliomas 1

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Amino Acids

Everolimus

Erlotinib Hydrochloride

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Tyrosine Kinase Inhibitors

Tyrosine

Each 28 day cycle:

RAD001: 5 mg per day by mouth (self-administered) Erlotinib: 100 mg per day by mouth (self-administered)

RAD001

erlotinib

Emily K. Bergsland, MD

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

RAD001 and Erlotinib in Patients With Neuroendocrine Tumors

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

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.

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 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 will be defined as the time from first day of treatment until death

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 disease progression will be defined as the time from baseline until documented disease progression or death (whichever occurs first).

Time to treatment failure will be defined as the time from first day of treatment until study discontinuation (for any cause).

Genentech, Inc.

Novartis Pharmaceuticals

The V Foundation for Cancer Research

University of California, San Francisco

Sponsor-Investigator

* everolimus 5 mg daily and continued this throughout the duration of treatment
* erlotinib at a dose of 100 mg daily with the option to dose reduce erlotinib to 100 mg daily in the setting of grade 3/4 rash or diarrhea
* cycles defined as every 28 days

RAD001 Plus Erlotinib

RAD001 and Erlotinib

20-29 years

30-39 years

40-49 years

50-59 years

60-69 years

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Carcinoid Neuroendocrine Tumor

Pancreatic neuroendocrine tumor (PNET)

Neuroendocrine Tumor Type

Study was terminated earlier than expected due to insufficient efficacy at interim analysis and overall low enrollment

Emily Bergsland, MD

Objective Response Rate (ORR)

Each 28 day cycle:

RAD001: 5 mg per day by mouth (self-administered) Erlotinib: 100 mg per day by mouth (self-administered)

RAD001: 5 mg/day PO (oral)

erlotinib: 100 mg/day (oral)

Number of Patients With Dose-limiting Toxicity (DLT)

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)

Duration of Objective Response

Overall Survival

No participants obtained an objective response (CR or PR) therefore data for long term progression-free survival data was not collected.

Spots Global Cancer Trial Database for pancreatic neuroendocrine