- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00843531
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
Study Overview
Status
Conditions
Intervention / Treatment
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).
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
California
-
San Francisco, California, United States, 94115
- University of California, San Francisco
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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 Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
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 Names:
100 mg/day (oral)
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
Up to 2 years
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
Up to 9 months
|
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
|
Up to 2 years
|
Overall Survival
Time Frame: Up to 3 years
|
Overall survival will be defined as the time from first day of treatment until death
|
Up to 3 years
|
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
|
Up to 3 years
|
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).
|
Up to 3 years
|
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).
|
Up to 3 years
|
Collaborators and Investigators
Investigators
- Principal Investigator: Emily K. Bergsland, MD, University of California, San Francisco
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Neuroendocrine Tumors
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Protein Kinase Inhibitors
- Erlotinib Hydrochloride
- Everolimus
Other Study ID Numbers
- 084511
- NCI-2011-01291 (Registry Identifier: NCI Clinical Trials Reporting Program (CTRP))
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Neuroendocrine Tumors
-
Jiangsu HengRui Medicine Co., Ltd.RecruitingAdvanced Gastroenteropancreatic Neuroendocrine TumorChina
-
Jiangsu HengRui Medicine Co., Ltd.Not yet recruitingAdvanced Gastroenteropancreatic Neuroendocrine Tumor
-
National Health Research Institutes, TaiwanNational Taiwan University Hospital; Mackay Memorial Hospital; China Medical... and other collaboratorsRecruitingNeuroendocrine Tumors,GastroenteropancreaticTaiwan
-
Grupo Espanol de Tumores NeuroendocrinosActive, not recruitingNeuroendocrine Tumors | Neuroendocrine Neoplasm | Gastroenteropancreatic Neuroendocrine TumorSpain
-
Amr Mohamed MDNovatek PharmaceuticalsRecruitingNeuroendocrine Carcinoma | Gastroenteropancreatic Neuroendocrine Tumor | Gastroenteropancreatic Neuroendocrine Neoplasm | Mixed Neuroendocrine-Non Neuroendocrine NeoplasmUnited States
-
Francesco De CobelliCompleted
-
Australasian Gastro-Intestinal Trials GroupCompletedMidgut Neuroendocrine Tumours | Pancreatic Neuroendocrine TumoursAustralia
-
TaiRx, Inc.Active, not recruitingNeuroendocrine Tumors | Gastro-enteropancreatic Neuroendocrine Tumor | Neuroendocrine Carcinoma | Pancreatic Neuroendocrine Tumor | Lung Neuroendocrine NeoplasmTaiwan
-
Memorial Sloan Kettering Cancer CenterRecruitingNeuroendocrine Tumors | Liver-Dominant Metastatic Pancreatic Neuroendocrine TumorsUnited States
-
University Hospital, Basel, SwitzerlandSwiss National Science Foundation; Paul Scherrer Institute (PSI)RecruitingNeuroendocrine Neoplasia's (NENs) | Gastroenteropancreatic Neuroendocrine Tumour (GEP-NET)Switzerland
Clinical Trials on RAD001
-
Children's Hospital Medical Center, CincinnatiNovartisCompletedTuberous Sclerosis | AngiolipomaUnited States
-
Novartis PharmaceuticalsCompletedMetastatic Renal Cell Carcinoma (mRCC)Germany
-
University of Alabama at BirminghamNational Cancer Institute (NCI); Children's Hospital of Philadelphia; Washington... and other collaboratorsCompleted
-
Novartis PharmaceuticalsCompleted
-
Novartis PharmaceuticalsCompletedLymphangioleiomyomatosis (LAM) | Tuberous Sclerosis Complex (TSC)United States, United Kingdom, Germany, Italy, Russian Federation, Netherlands, Japan, Canada, Poland, France, Spain
-
Radiation Therapy Oncology GroupNational Cancer Institute (NCI); NRG OncologyCompletedBrain and Central Nervous System TumorsUnited States, Israel, Canada
-
Guangdong Provincial People's HospitalNovartisUnknownNeuroendocrine Tumors | Carcinoid TumorChina
-
University of ChicagoNovartis PharmaceuticalsTerminatedNon-Small Cell Lung CancerUnited States
-
Fox Chase Cancer CenterRecruitingMetastatic Pancreatic CancerUnited States
-
Novartis PharmaceuticalsTerminatedHepatocellular CarcinomaUnited States, Spain, Korea, Republic of, Netherlands, Taiwan