RAD001 and Erlotinib in Patients With Neuroendocrine Tumors
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Purpose
The purpose of this study is to test how safe and effective the combination of RAD001 and erlotinib is in patients with neuroendocrine tumors.
| Condition | Intervention | Phase |
|---|---|---|
|
Neuroendocrine Tumors |
Drug: RAD001 Drug: erlotinib |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| 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 |
- 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 ] [ Designated as safety issue: No ]
- To determine the safety of RAD001 plus erlotinib in patients with progressive moderately- to well-differentiated NETs. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
- To determine overall survival. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
- To determine 6-month progression free survival (PFS). [ Time Frame: 3 years ] [ Designated as safety issue: No ]
- To determine time to treatment failure. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
- To determine time to progression. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
- To determine biochemical marker response rate by measuring chromogranin A levels (and other markers as indicated). [ Time Frame: 3 years ] [ Designated as safety issue: No ]
- 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 ] [ Designated as safety issue: No ]
- To assess ras mutational status. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
| Estimated Enrollment: | 44 |
| Study Start Date: | June 2009 |
| Estimated Study Completion Date: | March 2013 |
| Estimated Primary Completion Date: | January 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
| Experimental: RAD001 and erlotinib |
Drug: RAD001
5 mg/day PO (oral)
Other Name: everolimus
Drug: erlotinib
100 mg/day (oral)
Other Name: Tarceva
|
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 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).
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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
Contacts and Locations| United States, California | |
| UCSF Helen Diller Family Comprehensive Cancer Center | |
| San Francisco, California, United States, 94115 | |
| Principal Investigator: | Emily K. Bergsland, MD | University of California, San Francisco |
More Information
No publications provided
| Responsible Party: | University of California, San Francisco |
| ClinicalTrials.gov Identifier: | NCT00843531 History of Changes |
| Other Study ID Numbers: | 084511 |
| Study First Received: | February 12, 2009 |
| Last Updated: | October 9, 2012 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by University of California, San Francisco:
|
neuroendocrine islet cell carcinoid pancreatic neuroendocrine paraganglioma |
pheochromocytoma RAD001 everolimus erlotinib Tarceva |
Additional relevant MeSH terms:
|
Neuroendocrine Tumors Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Nerve Tissue Everolimus Sirolimus Erlotinib Immunosuppressive Agents Immunologic Factors |
Physiological Effects of Drugs Pharmacologic Actions Antibiotics, Antineoplastic Antineoplastic Agents Therapeutic Uses Antifungal Agents Anti-Infective Agents Anti-Bacterial Agents Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |
ClinicalTrials.gov processed this record on May 23, 2013