Everolimus in Patients With Pancreatic Neuroendocrine Tumors Metastatic to the Liver Previously Treated With Surgery
Condition: Gastrinoma; Glucagonoma; Insulinoma; Liver Metastases; Pancreatic Polypeptide Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma
MeSH terms: Neuroendocrine Tumors; Insulinoma; Carcinoma, Islet Cell; Gastrinoma; Glucagonoma; Somatostatinoma
Intervention: everolimus; placebo
Intervention description: Given PO; Given PO
Intervention MeSH terms: Everolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: everolimus; randomized; metastatic pancreatic neuroendocrine tumors; liver

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.
    

Eligibility 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

          -  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

          -  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 with a history of the following within =< 12 months of randomization are not
             eligible

               -  Arterial thromboembolic events

               -  Unstable angina

               -  Myocardial infarction

          -  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 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 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 have Eastern Cooperative Oncology Group (ECOG) performance status =< 1

          -  Patients must have life expectancy >= 12 weeks

          -  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

        EXCLUSION CRITERIA:

          -  Patients have received prior everolimus

          -  Patients have either clinically apparent central nervous system metastases or
             carcinomatous meningitis =< 6 months prior to randomization

          -  Women are pregnant or breast-feeding; all females of childbearing potential must have
             a blood test within 2 weeks prior to randomization to rule out pregnancy

          -  Patients are on chronic treatment with corticosteroids or other immunosuppressive
             agents; topical or inhaled corticosteroids are allowed

          -  Patients have history of allergic reactions attributed to compounds of similar
             chemical or biologic composition to everolimus

          -  Patients have known intolerance or hypersensitivity to everolimus or other rapamycin
             analogs (e.g. sirolimus, temsirolimus)

          -  Patients have absorption issues that would limit the ability to absorb everolimus

          -  Patients 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 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 have 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 have known history of human immunodeficiency virus (HIV) seropositivity

          -  Patients have experienced thrombotic events (deep vein thrombosis, pulmonary embolism)
             =< 3 months prior to randomization

          -  Patients 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 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 have history of severely impaired pulmonary function for their age