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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Eastern Cooperative Oncology Group
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Eastern Cooperative Oncology Group
ClinicalTrials.gov Identifier:
NCT02031536
First received: January 7, 2014
Last updated: July 24, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Gastrinoma
Glucagonoma
Insulinoma
Liver Metastases
Pancreatic Polypeptide Tumor
Recurrent Islet Cell Carcinoma
Somatostatinoma
Drug: everolimus
Other: placebo
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant Everolimus Following the Resection of Metastatic Pancreatic Neuroendocrine Tumors to the Liver

Resource links provided by NLM:


Further study details as provided by Eastern Cooperative Oncology Group:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Overall survival (OS) [ Time Frame: From randomization to death from any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 150
Study Start Date: January 2014
Estimated Study Completion Date: April 2017
Estimated Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: everolimus
Given PO
Other Names:
  • 42-O-(2-hydroxy)ethyl rapamycin
  • Afinitor
  • RAD001
Other: laboratory biomarker analysis
Correlative studies
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.
Other: placebo
Given PO
Other Name: PLCB
Other: laboratory biomarker analysis
Correlative studies

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02031536

Locations
United States, Massachusetts
Eastern Cooperative Oncology Group Recruiting
Boston, Massachusetts, United States, 02215
Contact: Steven K. Libutti    718-904-2730    aecc@aecom.yu.edu   
Principal Investigator: Steven K. Libutti         
Sponsors and Collaborators
Eastern Cooperative Oncology Group
Investigators
Principal Investigator: Steven Libutti Eastern Cooperative Oncology Group
  More Information

No publications provided

Responsible Party: Eastern Cooperative Oncology Group
ClinicalTrials.gov Identifier: NCT02031536     History of Changes
Other Study ID Numbers: E2212, NCI-2013-02484, ECOG-E2212, E2212, E2212, U10CA021115
Study First Received: January 7, 2014
Last Updated: July 24, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Insulinoma
Neuroendocrine Tumors
Adenoma, Islet Cell
Carcinoma, Islet Cell
Gastrinoma
Somatostatinoma
Glucagonoma
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Adenoma
Neoplasms, Glandular and Epithelial
Pancreatic Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Adenocarcinoma
Carcinoma
Carcinoma, Neuroendocrine
Everolimus
Sirolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 30, 2014