RAD001 and Erlotinib in Patients With Neuroendocrine Tumors

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00843531
• Collaborator: Genentech, Inc. (Industry), Novartis Pharmaceuticals (Industry), The V Foundation for Cancer Research (Other)
• Enrollment: 17
• Location: 1
• Arm: 1
• Actual Duration (Months): 85.8
• Patients Per Site Per Month: 0.2

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Neuroendocrine Tumors	Drug: RAD001; Drug: erlotinib	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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
• Actual Study Start Date: Jun 25, 2009
• Actual Primary Completion Date: Jul 16, 2013
• Actual Study Completion Date: Aug 20, 2016

Arms and Interventions

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)	Drug: RAD001; 5 mg/day PO (oral); Other Names: Everolimus ; Drug: erlotinib; 100 mg/day (oral); Other Names: Tarceva

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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

3. Overall Survival [Up to 3 years]

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

4. 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

5. 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).

6. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• 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

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco	San Francisco	California	United States	94115

Sponsors and Collaborators

• University of California, San Francisco
• Genentech, Inc.
• Novartis Pharmaceuticals
• The V Foundation for Cancer Research

Investigators

• Principal Investigator: Emily K. Bergsland, MD, University of California, San Francisco

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Emily Bergsland, Sponsor-Investigator, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT00843531
• Other Study ID Numbers: 084511; NCI-2011-01291
• First Posted: Feb 13, 2009
• Last Update Posted: Sep 29, 2020
• Last Verified: Sep 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Emily Bergsland, Sponsor-Investigator, University of California, San Francisco: neuroendocrine; islet cell; carcinoid; pancreatic neuroendocrine; paraganglioma; pheochromocytoma; RAD001; everolimus; erlotinib; Tarceva
• Additional relevant MeSH terms: Neuroendocrine Tumors; Everolimus; Erlotinib Hydrochloride

Study Results

Participant Flow

Arm/Group Title	RAD001 and Erlotinib
Arm/Group Description	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)
Period Title: Overall Study
STARTED	17
COMPLETED	17
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	RAD001 and Erlotinib
Arm/Group Description	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
Overall Participants	17
Age, Customized (Count of Participants)
20-29 years	1 5.9%
30-39 years	0 0%
40-49 years	2 11.8%
50-59 years	2 11.8%
60-69 years	12 70.6%
Sex: Female, Male (Count of Participants)
Female	8 47.1%
Male	9 52.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	16 94.1%
Unknown or Not Reported	1 5.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 5.9%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 5.9%
White	15 88.2%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	17 100%
Neuroendocrine Tumor Type (Count of Participants)
Carcinoid Neuroendocrine Tumor	9 52.9%
Pancreatic neuroendocrine tumor (PNET)	8 47.1%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR)
Description	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.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RAD001 Plus Erlotinib
Arm/Group Description	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
Measure Participants	17
Count of Participants [Participants]	0 0%

2. Secondary Outcome

Title	Number of Patients With Dose-limiting Toxicity (DLT)
Description	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.
Time Frame	Up to 9 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RAD001 and Erlotinib
Arm/Group Description	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)
Measure Participants	17
Count of Participants [Participants]	8 47.1%

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RAD001 and Erlotinib
Arm/Group Description	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)
Measure Participants	17
Number [months]	NA

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Data for overall survival not collected

Arm/Group Title	RAD001 and Erlotinib
Arm/Group Description	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)
Measure Participants	0

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RAD001 and Erlotinib
Arm/Group Description	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)
Measure Participants	0

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Data for time to progression not collected

Arm/Group Title	RAD001 Plus Erlotinib
Arm/Group Description	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)
Measure Participants	0

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Data for time to treatment failure not collected

Arm/Group Title	Carcinoid Tumors
Arm/Group Description	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
Measure Participants	0

Adverse Events

Time Frame	Up to 3 years
Arm/Group Title	RAD001 Plus Erlotinib
Arm/Group Description	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
All Cause Mortality
	RAD001 Plus Erlotinib
	Affected / at Risk (%)	# Events
Total	6/17 (35.3%)
Serious Adverse Events
	RAD001 Plus Erlotinib
	Affected / at Risk (%)	# Events
Total	4/17 (23.5%)
Gastrointestinal disorders
Diarrhea	1/17 (5.9%)	1
Pain - Abdomen NOS	1/17 (5.9%)	1
Distension/bloating, abdominal	1/17 (5.9%)	1
General disorders
Fever	1/17 (5.9%)	1
Investigations
Creatinine	1/17 (5.9%)	1
Alkaline phosphatase	1/17 (5.9%)	1
Pain - Other - Right upper quadrant pain	1/17 (5.9%)	1
Musculoskeletal and connective tissue disorders
Pain - Back	1/17 (5.9%)	1
Pain - Extremity-limb	1/17 (5.9%)	1
Renal and urinary disorders
Incontinence, urinary	1/17 (5.9%)	1
Renal failure	1/17 (5.9%)	1
Vascular disorders
Edema: limb	1/17 (5.9%)	2
Other (Not Including Serious) Adverse Events
	RAD001 Plus Erlotinib
	Affected / at Risk (%)	# Events
Total	17/17 (100%)
Blood and lymphatic system disorders
Lymphopenia	4/17 (23.5%)	4
Neutrophils/granulocytes	2/17 (11.8%)	12
Lymphopenia	2/17 (11.8%)	4
Platelets	2/17 (11.8%)	4
Cardiac disorders
Dyspnea	3/17 (17.6%)	3
Gastrointestinal disorders
Stomatitis	13/17 (76.5%)	41
Diarrhea	15/17 (88.2%)	36
Dry mouth	6/17 (35.3%)	8
Flatulence	5/17 (29.4%)	7
Vomiting	4/17 (23.5%)	10
Nausea	4/17 (23.5%)	9
Pain - Abdomen NOS	3/17 (17.6%)	4
Constipation	3/17 (17.6%)	3
Dysphagia	3/17 (17.6%)	3
Distension/bloating, abdominal	1/17 (5.9%)	3
General disorders
Fatigue	13/17 (76.5%)	21
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	4/17 (23.5%)	7
Chills	3/17 (17.6%)	3
Investigations
Weight Loss	9/17 (52.9%)	16
Hypercholesteremia	6/17 (35.3%)	8
AST, SGOT(serum glutamic oxaloacetic transaminase)	4/17 (23.5%)	11
Alkaline phosphatase	3/17 (17.6%)	7
Hemoglobin	3/17 (17.6%)	3
Metabolism and nutrition disorders
Anorexia	11/17 (64.7%)	14
Hypophosphatemia	7/17 (41.2%)	20
Dehydration	6/17 (35.3%)	10
Hyponatremia	5/17 (29.4%)	11
Hypomagnesemia	3/17 (17.6%)	7
Hyperglycemia	3/17 (17.6%)	5
Hypocalcemia	3/17 (17.6%)	3
Hyperuricemia	1/17 (5.9%)	2
Musculoskeletal and connective tissue disorders
Pain - Back	3/17 (17.6%)	4
Pain - Joint	1/17 (5.9%)	2
Nervous system disorders
Dysgeusia	9/17 (52.9%)	11
Pain - Head/headache	4/17 (23.5%)	4
Syncope	1/17 (5.9%)	1
Renal and urinary disorders
Creatinine	6/17 (35.3%)	15
Reproductive system and breast disorders
Cough	2/17 (11.8%)	2
Respiratory, thoracic and mediastinal disorders
Hemorrhage, pulmonary/upper respiratory - Nose	9/17 (52.9%)	13
Skin and subcutaneous tissue disorders
Rash: acne/acneiform	11/17 (64.7%)	24
Rash/desquamation	5/17 (29.4%)	8
Dry Skin	11/17 (64.7%)	13
Pruritus	9/17 (52.9%)	10
Nail changes	6/17 (35.3%)	11
Alopecia	5/17 (29.4%)	7
Vascular disorders
Edema: limb	4/17 (23.5%)	11
Hypotension	1/17 (5.9%)	1
Thrombosis/embolism	1/17 (5.9%)	1

Limitations/Caveats

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

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.