Capecitabine, Temozolomide, and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors
Condition: Gastrinoma; Glucagonoma; Insulinoma; Pancreatic Polypeptide Tumor; Recurrent Islet Cell Carcinoma; Recurrent Pancreatic Cancer; Somatostatinoma; Stage III Pancreatic Cancer; Stage IV Pancreatic Cancer
MeSH terms: Pancreatic Neoplasms; Neuroendocrine Tumors; Insulinoma; Carcinoma, Islet Cell; Gastrinoma; Glucagonoma; Somatostatinoma; Recurrence
Intervention: Capecitabine; Temozolomide; Bevacizumab
Intervention description: Capecitabine by mouth twice daily on Days 1 to 14; Temozolomide by mouth daily on Days 10 to 14; Bevacizumab IV over 30 to 90 minutes on Days 1 & 15
Intervention MeSH terms: Bevacizumab; Antineoplastic Agents, Immunological; Capecitabine; Temozolomide; Antibodies; Immunoglobulins; Antibodies, Monoclonal
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of this research is to evaluate the effectiveness and safety of a combination of
      capecitabine, temozolomide and bevacizumab in the treatment of advanced pancreatic
      neuroendocrine tumors.
    

Eligibility criteria:

        INCLUSION CRITERIA

          -  Histologically-confirmed pancreatic neuroendocrine tumors that are moderately- or
             well-differentiated

          -  Metastatic or unresectable disease

          -  If prior surgical resection > 5 years before the development of metastatic disease, a
             separate (recent) histological or cytological confirmation of metastatic disease is
             required

          -  If there is substantial clinical ambiguity regarding the nature or source of apparent
             metastases, clinicians should consider biopsy of lesions to establish diagnosis of
             metastatic disease

          -  The site of previous radiotherapy, if the only site of disease, has evidence of
             progressive disease

          -  If prior sunitinib and everolimus has been administered, a 2-week wash-out period is
             required prior to 1st dose on this study

          -  If prior liver-directed therapies (ie, chemoembolization, radioembolization), target
             lesions in the liver have demonstrated growth since the liver-directed treatment

          -  If prior peptide receptor radionuclide therapy (PRRT), target lesions in the liver
             have demonstrated growth since the liver-directed treatment

          -  Low-dose aspirin (≤ 325 mg/d) may be continued in subjects at higher risk for arterial
             thromboembolic disease.

          -  Primary or metastatic tumor lesion measurable in at least 1 dimension, within 4 weeks
             prior to entry of study.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

          -  ≥ 18 years of age.

          -  Laboratory values as follows, ≤ 2 weeks prior to randomization:

          -  Absolute neutrophil count (ANC) ≥ 1.5 x 10e9/L (≥ 1500/mm³)

          -  Platelets (PLT) ≥ 100 x 10e9/L (≥ 100,000/mm³)

          -  Hemoglobin (Hgb) ≥ 9 g/dL

          -  Serum creatinine ≤ 1.5 x upper limit of normal (ULN)

          -  Serum bilirubin ≤ 1.5 x ULN

          -  Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT) ≤ 3.0 x ULN
             (≤ 5.0 x ULN if liver metastases present). Note: endoscopic retrograde
             cholangiopancreatography (ERCP) or percutaneous stenting may be used to normalize the
             liver function tests

          -  Urine dipstick or urinalysis for protein, value must be 0, trace, or 1+ protein to
             enroll. EXCEPTION: if ≥ 2+ must check 24-hour urine protein and must be < 1 g

          -  Life expectancy ≥ 12 weeks

          -  Ability to give written informed consent according to local guidelines

          -  If any prior therapy-related toxicities, must have recovered from all

        EXCLUSION CRITERIA Disease-Specific Exclusions

          -  Prior bevacizumab; fluoropyrimidines (eg, capecitabine or 5-fluorouracil, 5FU); or
             temozolomide

          -  Poorly-differentiated or high-grade pancreatic neuroendocrine tumors

          -  Prior full field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior
             to enrollment

          -  Diagnosis of another malignancy, unless > 3 years earlier and has been disease-free
             for > 6 months following the completion of curative intent therapy, specific
             eligibility exceptions as follows:

          -  Curatively-resected non-melanomatous skin cancer

          -  Curatively-treated cervical carcinoma in situ

          -  Organ-confined prostate cancer with no evidence of recurrent or progressive disease
             based on prostate-specific antigen (PSA) values, if hormonal therapy has been
             initiated or a radical prostatectomy has been performed

          -  Other primary solid tumor curatively treated with no known active disease present and
             no treatment administered for > 3 years

          -  Concurrent use of other investigational agents and patients who have received
             investigational drugs ≤ 4 weeks prior to enrollment

          -  Known hypersensitivity to capecitabine, temozolomide, or any component of the
             formulation

          -  Known deficiency of dihydropyrimidine dehydrogenase Bevacizumab-specific Exclusions

          -  Inadequately-controlled hypertension (defined as systolic blood pressure >150 mmHg
             and/or diastolic blood pressure > 100 mmHg)

          -  Prior history of hypertensive crisis or hypertensive encephalopathy

          -  New York Heart Association (NYHA) Grade II or greater congestive heart failure

          -  History of myocardial infarction or unstable angina within 6 months prior to Day 1

          -  History of stroke or transient ischemic attack within 6 months prior to Day 1

          -  Known central nervous system (CNS) metastases

          -  Significant vascular disease (eg, aortic aneurysm, requiring surgical repair or recent
             peripheral arterial thrombosis) within 6 months prior to Day 1

          -  History of hemoptysis (≥ ½ teaspoon of bright red blood per episode) within 1 month
             prior to Day 1

          -  Evidence of bleeding diathesis or significant coagulopathy (in the absence of
             therapeutic anticoagulation)

          -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to Day 1 or anticipation of need for major surgical procedure during the course
             of the study

          -  Core biopsy or other minor surgical procedure, excluding placement of a vascular
             access device, within 7 days prior to Day 1

          -  History of abdominal fistula or gastrointestinal perforation within 6 months prior to
             Day 1

          -  Serious, non-healing wound, active ulcer, or untreated bone fracture

          -  Known hypersensitivity to any component of bevacizumab General Medical Exclusions

          -  Inability to comply with study and/or follow-up procedures

          -  Current, recent (within 4 weeks of the first infusion of this study), or planned
             participation in an experimental drug study

          -  Pregnant or lactating/breast feeding

          -  Lack of effective contraception men or women of child-bearing potential

          -  Uncontrolled systemic fungal, bacterial, viral, or other infection (defined as
             exhibiting ongoing signs/symptoms related to the infection and without improvement,
             despite appropriate antibiotics or other treatment)

          -  Known history of HIV, HBV, or HCV

          -  Current, ongoing treatment with full-dose warfarin. However, patients may be on stable
             doses of a low-molecular weight heparin are allowed [eg, (enoxaparin (Lovenox)].