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Everolimus in Patients With Pancreatic Neuroendocrine Tumors Metastatic to the Liver Previously Treated With Surgery

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02031536
Recruitment Status : Terminated (Slow accrual)
First Posted : January 9, 2014
Last Update Posted : February 9, 2017
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Eastern Cooperative Oncology Group

Tracking Information
First Submitted Date  ICMJE January 7, 2014
First Posted Date  ICMJE January 9, 2014
Last Update Posted Date February 9, 2017
Study Start Date  ICMJE January 2014
Actual Primary Completion Date February 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 7, 2014)
Disease free survival (DFS) [ Time Frame: From randomization to the earlier of documented recurrence (a return of tumor imaged by CT or MRI, new invasive primary cancer, or death without recurrence), assessed up to 5 years ]
Kaplan-Meier estimates will be used. DFS by arm will be compared using one-sided stratified log-rank tests. Cox's proportional hazards models will be used to estimate hazard ratios.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 7, 2014)
Overall survival (OS) [ Time Frame: From randomization to death from any cause, assessed up to 5 years ]
Kaplan-Meier estimates will be used. OS by arm will be compared using one-sided stratified log-rank tests. Cox's proportional hazards models will be used to estimate hazard ratios.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Everolimus in Patients With Pancreatic Neuroendocrine Tumors Metastatic to the Liver Previously Treated With Surgery
Official Title  ICMJE A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant Everolimus Following the Resection of Metastatic Pancreatic Neuroendocrine Tumors to the Liver
Brief Summary This randomized phase II trial studies how well everolimus works in treating patients with pancreatic neuroendocrine tumors metastatic to the liver previously treated with surgery. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving everolimus after surgery may kill any tumors cells that remain.
Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate if the addition of adjuvant everolimus to the R0 or R1 surgical resection of pancreatic neuroendocrine tumor metastases to the liver will result in an improvement in disease free survival.

SECONDARY OBJECTIVES:

I. To evaluate if the addition of adjuvant everolimus to the R0 or R1 surgical resection of pancreatic neuroendocrine tumor metastases to the liver will result in an improvement in overall survival.

II. To evaluate the toxicity associated with adjuvant everolimus following resection in patients with metastatic pancreatic neuroendocrine tumors to the liver.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive everolimus orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive placebo PO QD on days on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double
Primary Purpose: Treatment
Condition  ICMJE
  • Gastrinoma
  • Glucagonoma
  • Insulinoma
  • Liver Metastases
  • Pancreatic Polypeptide Tumor
  • Recurrent Islet Cell Carcinoma
  • Somatostatinoma
Intervention  ICMJE
  • Drug: everolimus
    Given PO
    Other Names:
    • 42-O-(2-hydroxy)ethyl rapamycin
    • Afinitor
    • RAD001
  • Other: placebo
    Given PO
    Other Name: PLCB
  • Other: laboratory biomarker analysis
    Correlative studies
Study Arms  ICMJE
  • Experimental: Arm A (everolimus)
    Patients receive everolimus PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: everolimus
    • Other: laboratory biomarker analysis
  • Placebo Comparator: Arm B (placebo)
    Patients receive placebo PO QD on days on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Other: placebo
    • Other: laboratory biomarker analysis
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: February 7, 2017)
2
Original Estimated Enrollment  ICMJE
 (submitted: January 7, 2014)
150
Estimated Study Completion Date  ICMJE April 2017
Actual Primary Completion Date February 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must have histologically or pathologically confirmed metastatic low or intermediate grade pancreatic neuroendocrine tumor(s) to the liver as per the Klimstra guidelines
  • Patients must have recovered from an R0 or R1 resection of all disease (including resection of a primary primitive neuroectodermal tumor [PNET] if present); patients may have had resection plus microwave or radiofrequency ablation, provided that no ablated lesion was >= 5 cm prior to ablation
  • Patients must be within 4 to 8 weeks from the completion of surgery at time of randomization
  • Patients must have paraffin-embedded fixed metastatic tumor tissue available for submission for central review; core biopsy or surgical specimens required
  • Patients must have post-operative computed tomography (CT) or magnetic resonance imaging (MRI) prior to randomization and =< 4 weeks after completion of surgery to confirm disease status; patients must be able to tolerate CT or MRI imaging including contrast agents as required for the protocol
  • Patients must NOT have either clinically apparent central nervous system metastases or carcinomatous meningitis =< 6 months prior to randomization
  • Women must NOT be pregnant or breast-feeding; all females of childbearing potential must have a blood test within 2 weeks prior to randomization to rule out pregnancy
  • Women of child-bearing potential and sexually active males must be strongly advised to use an accepted and highly effective method of contraception or abstain from sexual intercourse for the duration of their treatment through 8 weeks after their last dose of protocol therapy; women of child-bearing potential, sexually active males, and the female partners of male participants should be advised of the risk of becoming pregnant or fathering a child while receiving protocol treatment; should a woman become pregnant while participating in this study, she should inform her treating physician immediately; if a man impregnates a woman while participating in this study, he should inform his treating physician immediately
  • Prior treatment with sunitinib and/or cytotoxic chemotherapy are allowed provided last dose was > 30 days prior to randomization
  • Prior chemoembolization is allowed provided last dose was > 30 days prior to randomization
  • Patients must NOT have received prior everolimus
  • Total bilirubin =< 1.5 X institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 X institutional ULN
  • Serum creatinine =< 1.5 X institutional ULN or creatinine clearance >= 60 mL/min for patients with creatinine levels above 1.5 X institutional normal
  • Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =< 2.5 x ULN
  • Absolute neutrophil count >= 1,500/mm^3
  • Leukocytes >= 3,000/mm^3
  • Platelets >= 100,000/mm^3
  • Hemoglobin >= 9 g/dL
  • Patients must NOT have ongoing cardiac dysrhythmia of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (v4.0) grade >= 2, uncontrolled atrial fibrillation of any grade, or corrected QT (QTc) interval > 470 msec
  • Patients with a history of the following within =< 12 months of randomization are not eligible

    • Arterial thromboembolic events
    • Unstable angina
    • Myocardial infarction
  • Patients must NOT have experienced thrombotic events (deep vein thrombosis, pulmonary embolism) =< 3 months prior to randomization
  • Patients must NOT have liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis at randomization; patients at increased risk for hepatitis B or hepatitis C must be screened for hepatitis prior to randomization
  • Patients must NOT have history of severely impaired pulmonary function for their age; patients with known history of abnormal pulmonary function must have documentation of diffusing capacity of the lung for carbon monoxide (DLCO) of > 50% predicted and oxygen saturation (SaO2) of > 87% at rest on room air =< 4 weeks prior to randomization
  • Patients with unexplained pulmonary infiltrates must have pulmonary function tests within the institutional limits of normal =< 4 weeks prior to randomization
  • Patients with known history of human immunodeficiency virus (HIV) seropositivity are ineligible
  • Patients with poorly controlled diabetes mellitus as defined by hemoglobin A1c (HbA1c) > 8% despite adequate therapy are ineligible; patients with a known history of impaired fasting glucose or diabetes mellitus must have blood glucose and antidiabetic treatment monitored closely throughout the trial and adjusted as necessary
  • Patients must NOT have any severe and/or uncontrolled medical conditions such as:

    • Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction =< 6 months prior to randomization, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease
    • Symptomatic congestive heart failure of New York Heart Association class III or IV
    • Active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable hepatitis B virus [HBV]-deoxyribonucleic acid [DNA] and/or positive hepatitis B surface antigen [HbsAg], quantifiable hepatitis C virus [HCV]-ribonucleic acid [RNA])
    • Active, bleeding diathesis
  • Patients must NOT have previous or concurrent malignancy; exceptions are made for patients who meet any of the following conditions:

    • Non-melanoma skin cancer, in situ cervical cancer, breast cancer in situ, or superficial bladder cancer (noninvasive papillary carcinoma or carcinoma in situ); OR
    • Prior malignancy completely excised or removed and patient has been continuously disease free for > 5 years
  • Patients may not be receiving any other investigational agents while on study treatment; prior treatment with other investigational agent is allowed provided last dose was >= 30 days prior to randomization
  • Patients must NOT have received live attenuated vaccines =< 1 week prior to randomization; patients should also be advised not to receive live attenuated vaccines during the study and to avoid close contact with others who have received live attenuated vaccines; examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus Calmette-Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines
  • Patients must NOT be on chronic treatment with corticosteroids or other immunosuppressive agents; topical or inhaled corticosteroids are allowed
  • Patients should be advised to avoid drugs or foods that are known potent cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors or inducers
  • Patients must NOT have history of allergic reactions attributed to compounds of similar chemical or biologic composition to everolimus
  • Patients must NOT have known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus)
  • Patients must NOT have absorption issues that would limit the ability to absorb everolimus
  • Patients must NOT have a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study
  • Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Patients must have life expectancy >= 12 weeks
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02031536
Other Study ID Numbers  ICMJE E2212
NCI-2013-02484 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ECOG-E2212 ( Other Identifier: ECOG )
E2212 ( Other Identifier: Eastern Cooperative Oncology Group )
E2212 ( Other Identifier: CTEP )
U10CA021115 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Eastern Cooperative Oncology Group
Study Sponsor  ICMJE Eastern Cooperative Oncology Group
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Steven Libutti Eastern Cooperative Oncology Group
PRS Account Eastern Cooperative Oncology Group
Verification Date February 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP