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RAD001 and Erlotinib in Patients With Neuroendocrine Tumors

Primary Purpose

Neuroendocrine Tumors

Status

Terminated

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

RAD001

erlotinib

About this trial

This is an interventional treatment trial for Neuroendocrine Tumors focused on measuring neuroendocrine, islet cell, carcinoid, pancreatic neuroendocrine, paraganglioma, pheochromocytoma, RAD001, everolimus, erlotinib, Tarceva

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

University of California, San Francisco

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

RAD001 and erlotinib

Arm Description

Each 28 day cycle: RAD001: 5 mg per day by mouth (self-administered) Erlotinib: 100 mg per day by mouth (self-administered)

Outcomes

Primary Outcome Measures

Objective Response Rate (ORR)

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

Number of Patients With Dose-limiting Toxicity (DLT)

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

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

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

Median Progression-Free Survival (PFS)

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

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)

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

Full Information

NCT ID

NCT00843531

First Posted

February 12, 2009

Last Updated

September 27, 2020

Sponsor

University of California, San Francisco

Collaborators

Genentech, Inc., Novartis Pharmaceuticals, The V Foundation for Cancer Research

1. Study Identification

Unique Protocol Identification Number

NCT00843531

Brief Title

RAD001 and Erlotinib in Patients With Neuroendocrine Tumors

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2020

Overall Recruitment Status

Terminated

Why Stopped

Low Accrual

Study Start Date

June 25, 2009 (Actual)

Primary Completion Date

July 16, 2013 (Actual)

Study Completion Date

August 20, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of California, San Francisco

Collaborators

Genentech, Inc., Novartis Pharmaceuticals, The V Foundation for Cancer Research

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Neuroendocrine Tumors

Keywords

neuroendocrine, islet cell, carcinoid, pancreatic neuroendocrine, paraganglioma, pheochromocytoma, RAD001, everolimus, erlotinib, Tarceva

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

17 (Actual)

8. Arms, Groups, and Interventions

Arm Title

RAD001 and erlotinib

Arm Type

Experimental

Arm Description

Each 28 day cycle: RAD001: 5 mg per day by mouth (self-administered) Erlotinib: 100 mg per day by mouth (self-administered)

Intervention Type

Drug

Intervention Name(s)

RAD001

Other Intervention Name(s)

Everolimus

Intervention Description

5 mg/day PO (oral)

Intervention Type

Drug

Intervention Name(s)

erlotinib

Other Intervention Name(s)

Tarceva

Intervention Description

100 mg/day (oral)

Primary Outcome Measure Information:

Title

Objective Response Rate (ORR)

Description

Time Frame

Up to 2 years

Secondary Outcome Measure Information:

Title

Number of Patients With Dose-limiting Toxicity (DLT)

Description

Time Frame

Up to 9 months

Title

Duration of Objective Response

Description

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

Time Frame

Up to 2 years

Title

Overall Survival

Description

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

Time Frame

Up to 3 years

Title

Median Progression-Free Survival (PFS)

Description

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 Frame

Up to 3 years

Title

Time to Progression

Description

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

Time Frame

Up to 3 years

Title

Time to Treatment Failure (TTF)

Description

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

Time Frame

Up to 3 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Emily K. Bergsland, MD

Organizational Affiliation

University of California, San Francisco

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of California, San Francisco

City

San Francisco

State/Province

California

ZIP/Postal Code

94115

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

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RAD001 and Erlotinib in Patients With Neuroendocrine Tumors

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