Avastin (Bevacizumab) and RAD001 (Everolimus) in Advanced Low or Intermediate Grade Neuroendocrine Carcinoma
Condition: Neuroendocrine Carcinoma
MeSH terms: Carcinoma; Carcinoma, Neuroendocrine
Intervention: Avastin; RAD001
Intervention description: 15 mg/kg By Vein Over 90 Minutes Every 21 Days; 10 mg By Mouth Daily For 21 Days
Intervention MeSH terms: Bevacizumab; Everolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 41.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Neuroendocrine Carcinoma; Avastin; Bevacizumab; RAD001; Everolimus

Summary:

      Primary Objectives:

        -  To determine the effect of Avastin on tumor blood flow as determined by functional
           computed tomography (CT) in patients with low or intermediate grade neuroendocrine
           carcinoma.

        -  To determine the effect of RAD001 on tumor blood flow as determined by functional CT in
           patients with low or intermediate grade neuroendocrine carcinoma.

        -  To determine the effect of adding the second agent (Avastin or RAD001) to the first
           agent (RAD001 or Avastin) on tumor blood flow as determined by functional CT

      Secondary Objectives:

        -  To determine the clinical activity (objective response rate and progression free
           survival duration) of Avastin and RAD001 in patients with low or intermediate grade
           neuroendocrine carcinoma.

        -  To determine the biochemical response rate of Avastin and RAD001 in patients with low or
           intermediate grade neuroendocrine carcinoma.

        -  To determine the safety and tolerability of Avastin and RAD001 in patients with low or
           intermediate grade neuroendocrine carcinoma.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients must have histologically or cytologically confirmed low or intermediate grade
             neuroendocrine carcinoma. Patients with neuroendocrine tumors associated with MEN1
             syndrome will be eligible.

          2. Patients must have at least one measurable site of disease according to Response
             Evaluation Criteria in Solid Tumors (RECIST) that has not been previously irradiated.
             If the patient has had previous radiation to the target lesion(s), there must be
             evidence of progression in the lesion(s) since the radiation.

          3. Patients must have at least one lesion suitable for perfusion CT. The lesion should be
             greater than or equal to 3 cm in size in the cranial caudal direction.

          4. Patients who are on a somatostatin analogue must be on a stable dose (no change in mg
             dose of long acting octreotide or lanreotide, changes in dosing interval of +/- 1 week
             is allowed) for 2 months prior to date of randomization.

          5. Prior radiation therapy is permitted. A recovery period of at least 4 weeks after
             completion of radiotherapy is required prior to date of randomization.

          6. Patients may have received prior interferon or cytotoxic chemotherapy. There are no
             limitations on the number of prior regimens. Patients who had no prior therapy are
             eligible. At least 28 days must have elapsed since last treatment.

          7. Patients may have received prior therapy targeting c-kit, abl, Platelet Derived Growth
             Factor Receptor (PDGFR), or estimated glomerular filtration rate or epidermal growth
             factor receptor (EGFR) (imatinib, gefitinib, erlotinib, cetuximab).

          8. Age >/= 18 years of age, because no dosing or adverse event data are currently
             available on the use of bevacizumab and everolimus in patients < 18 years of age.

          9. Patients must have unresectable or metastatic disease.

         10. Zubrod performance status of 0 or 1.

         11. Patients must have adequate organ and marrow function as defined below: Leukocytes >/=
             3,000/mcL; absolute neutrophil count >/=1,500/mcL; platelets >/=120,000 /mcL; total
             bilirubin </=1.5 times the institutional upper limit of normal (ULN); aspartate
             aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) </=3.0 times
             institutional ULN (</= 5 * ULN in patients with liver metastases); creatinine </= 2.0
             OR, creatinine clearance >/= 60 mL/min/1.73 m2 for patients with creatinine levels
             above institutional normal

         12. Patients not on anticoagulation must have Prothrombin time (PT)/partial thromboplastin
             time (PTT) within 1.2 * the upper limit of normal.

         13. Patients on full-dose anticoagulation (warfarin or low molecular weight heparin) are
             eligible provided that both of the following criteria are met: The patient has an
             in-range INR (between 2 and 3) on a stable (no change in the prior 2 weeks) dose of
             oral anticoagulant or on a stable (no change in the prior 2 weeks) dose of low
             molecular weight heparin. The patient has no active bleeding or known pathological
             condition that carries a high risk of bleeding such as varices.

         14. Patients must have resting blood pressure (BP) no greater than 140 mmHg (systolic) or
             90 mmHg (diastolic) for eligibility. Initiation or adjustment of BP medication is
             permitted prior to date of randomization.

         15. Women of child-bearing potential must have a negative urine pregnancy test within 7
             days prior to date of randomization. Women who have had menses within the past 2
             years, who have not had a hysterectomy, bilateral tubal ligation, or bilateral
             oophorectomy are considered to be of child-bearing potential.

         16. Ability to understand and the willingness to sign a written informed consent document
             and ability to comply with study and/or follow-up procedures.

         17. Men and women of reproductive potential must use effective means of contraception.
             Oral, implantable, or injectable contraceptives may be affected by cytochrome P450
             interactions, and are therefore not considered effective for this study. Barrier
             method of contraception is required during the study. Contraception should continue
             for 6 months after the last dose of bevacizumab.

        Exclusion Criteria:

          1. Current, recent (within 4 weeks of the first infusion of this study), or planned
             participation in an experimental drug study.

          2. Prior treatment with a mTOR inhibitor or bevacizumab.

          3. Chronic treatment with systemic steroids or another immunosuppressive agent.

          4. A known history of immunocompromise, including a positive HIV test. An HIV test will
             not be required; however, previous medical history will be reviewed.

          5. Inadequately controlled hypertension (defined as systolic blood pressure >140 and/or
             diastolic blood pressure > 90 mmHg on antihypertensive medications).

          6. Any prior history of hypertensive crisis or hypertensive encephalopathy.

          7. New York Heart Association (NYHA) Grade II or greater congestive heart failure.

          8. History of myocardial infarction or unstable angina within 6 months prior to date of
             randomization.

          9. History of stroke or transient ischemic attack within 6 months prior to date of
             randomization.

         10. Known history of brain or leptomeningeal metastases.

         11. Significant vascular disease (e.g., aortic aneurysm, aortic dissection).

         12. Symptomatic peripheral vascular disease.

         13. Evidence of bleeding diathesis or coagulopathy.

         14. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to date of randomization or anticipation of need for major surgical procedure
             during the course of the study.

         15. Minor surgical procedure, excluding placement of a vascular access device, within 7
             days prior to date of randomization.

         16. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
             within 6 months prior to date of randomization.

         17. Serious, non-healing wound, ulcer, or bone fracture.

         18. Proteinuria at screening as demonstrated by either: urine protein:creatinine (UPC)
             ratio >/= 1.0 at screening, OR, Urinalysis for proteinuria >/= 2+ (patients discovered
             to have>/= 2+ proteinuria on urinalysis at baseline should undergo a 24 hour urine
             collection and must demonstrate </= 1g of protein in 24 hours to be eligible).

         19. Known hypersensitivity to any component of bevacizumab.

         20. Pregnant or lactating. Should a woman become pregnant or suspect she is pregnant while
             participating in this study, she should inform her treating physician immediately.