Phase II Capecitabine, Oxaliplatin & Bevacizumab for Metastatic / Unresectable Neuroendocrine Tumors
Condition: Neuroendocrine Tumors
MeSH terms: Neuroendocrine Tumors
Intervention: Capecitabine; Oxaliplatin; Bevacizumab
Intervention description: 850 mg/m2 by mouth twice a day for days 1-14 oa a 21 day cycle; 130 mg/m2 intravenously on day 1 of a 21 day cycle; 7.5mg/kg Intravenous on day 1 of a 21 day cycle
Intervention MeSH terms: Bevacizumab; Capecitabine; Oxaliplatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 40.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Given the lack of other viable treatment options for metastatic neuroendocrine tumors,
      contrasted with our positive anecdotal experience, and the relative tolerability of the
      treatment regimen for colorectal cancer patients, we propose a single-institution phase II
      trial investigating the efficacy of capecitabine, oxaliplatin and bevacizumab for patients
      with metastatic neuroendocrine tumors.
    

Eligibility criteria:

        Inclusion Criteria: Subjects must be treated at Stanford University Medical Center for the
        entire length of study participation.

          -  Patients must have histologically or cytologically confirmed neuroendocrine tumor,
             including both well-differentiated tumors (carcinoid) or moderately to poorly
             differentiated tumors. Patients must be deemed unresectable due to involvement of
             critical vasculature, adjacent organ invasion, or presence of metastasis.

          -  Patients with prior surgical resection who develop radiological or clinical evidence
             of metastatic cancer do not require separate histological or cytological confirmation
             of metastatic disease unless an interval of > 5 years has elapsed between the primary
             surgery and the development of metastatic disease. Clinicians should consider biopsy
             of lesions to establish diagnosis of metastatic disease if there is substantial
             clinical ambiguity regarding the nature or source of apparent metastases.

          -  Prior chemotherapy will be permitted, although the patient may not have had prior
             oxaliplatin.

          -  Patients must have a primary or metastatic lesion measurable in at least one dimension
             by Modified RECIST criteria (see Section 4.2) within 4 weeks prior to entry of study

          -  Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0
             to 2

          -  Patients must be ≥ 18 years of age

          -  Laboratory values ≤ 2 weeks prior to randomization:

               -  Absolute Neutrophil Count (ANC) >=1500/mm3

               -  Platelets (PLT) ≥ 100,000/mm3

               -  Hemoglobin (Hgb) ≥ 9 g/dL

               -  Serum creatinine ≤ 1.5 x upper limit of normal (ULN)

               -  Serum bilirubin ≤ 1.5 x ULN (≤ 3.0 x ULN if liver metastases present)

               -  Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), and
                  alkaline phosphatase ≤ 3.0 x ULN (≤ 5.0 x ULN if liver metastases present). Note:
                  Endoscopic retrograde cholangiopancreatogram (ERCP) or percutaneous stenting may
                  be used to normalize the liver function tests.

          -  Life expectancy ≥ 12 weeks

          -  Ability to give written informed consent according to local guidelines

        Exclusion Criteria:- Disease-Specific Exclusions

          1. Prior oxaliplatin for any reason.

          2. Prior full field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior
             to enrollment. Patients must have recovered from all therapy-related toxicities. The
             site of previous radiotherapy should have evidence of progressive disease if this is
             the only site of disease.

          3. Prior biologic or immunotherapy ≤ 2 weeks prior to registration. Patients must have
             recovered from all therapy-related toxicities

          4. Prior therapy with anti-vascular endothelial growth factor (VEGF) agents

          5. If history of other primary cancer, subject will be eligible only if she or he has:

               -  Curatively resected non-melanomatous skin cancer

               -  Curatively treated cervical carcinoma in situ

               -  Other primary solid tumor curatively treated with no known active disease present
                  and no treatment administered for the last 3 years

          6. Concurrent use of other investigational agents and patients who have received
             investigational drugs ≤ 4 weeks prior to enrollment.

               -  General Medical Exclusions

        1. Subjects known to have chronic or active hepatitis B or C infection 2. History of any
        medical or psychiatric condition or laboratory abnormality that in the opinion of the
        investigator may increase the risks associated with study participation or study drug
        administration or may interfere with the conduct of the study or interpretation of study
        results 3. Male subject who is not willing to use adequate contraception upon enrollment
        into this study and for 6 months following the last dose of second-line treatment 4. Female
        subject (of childbearing potential, post-menopausal for less than 6 months, not surgically
        sterilized, or not abstinent) who is not willing to use an oral, patch or implanted
        contraceptive, double-barrier birth control, or an intrauterine device (IUD) during the
        course of the study and for 6 months following the last dose of second-line treatment 5.
        Female subject who is breast-feeding or who has positive serum pregnancy test 72 hours
        prior to randomization 6. Pleural effusion or ascites that causes respiratory compromise (≥
        CTCAE grade 2 dyspnea) 7. Any of the following concurrent severe and/or uncontrolled
        medical conditions within 24 weeks of enrollment which could compromise participation in
        the study:

          -  Unstable angina pectoris

          -  Symptomatic congestive heart failure

          -  Myocardial infarction ≤ 6 months prior to registration and/or randomization

          -  Serious uncontrolled cardiac arrhythmia

          -  Uncontrolled diabetes

          -  Active or uncontrolled infection

          -  Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung

          -  Chronic renal disease

          -  Acute or chronic liver disease (eg, hepatitis, cirrhosis) 8. Patients unwilling to or
             unable to comply with the protocol 9. Life expectancy of less than 12 weeks 10.
             Current, recent (within 4 weeks of the first infusion of this study), or planned
             participation in an experimental drug study other than a Genentech-sponsored
             bevacizumab cancer study

               -  Bevacizumab-Specific Exclusions

                    1. Inadequately controlled hypertension (defined as systolic blood pressure >
                       150 and/or diastolic blood pressure > 100 mmHg on antihypertensive
                       medications)

                    2. Any prior history of hypertensive crisis or hypertensive encephalopathy

                    3. New York Heart Association (NYHA) Grade II or greater congestive heart
                       failure (see Appendix E)

                    4. History of myocardial infarction or unstable angina within 6 months prior to
                       study enrollment

                    5. History of stroke or transient ischemic attack within 6 months prior to
                       study enrollment

                    6. Known central nervous system (CNS) disease

                    7. Significant vascular disease (eg, aortic aneurysm, aortic dissection)

                    8. Symptomatic peripheral vascular disease

                    9. Evidence of bleeding diathesis or coagulopathy

                   10. Major surgical procedure, open biopsy, or significant traumatic injury
                       within 28 days prior to study enrollment or anticipation of need for major
                       surgical procedure during the course of the study

                   11. Core biopsy or other minor surgical procedure, excluding placement of a
                       vascular access device, within 7 days prior to study enrollment

                   12. History of abdominal fistula, gastrointestinal perforation, or
                       intra-abdominal abscess within 6 months prior to study enrollment

                   13. Serious, non-healing wound, ulcer, or bone fracture

                   14. Urine protein ≥ 2+ on urinalysis dipstick and ≥ 1.0 gram on 24-hour urine
                       collection

                   15. Known hypersensitivity to any component of bevacizumab