Efficacy Study of Sorafenib and Cyclophosphamide to Treat Neuroendocrine Tumors
Condition: Neuroendocrine Tumors
MeSH terms: Neuroendocrine Tumors
Intervention: Sorafenib; Cyclophosphamide
Intervention description: During a run-in period, patient will start taking 50 mg QD of oral cyclophosphamide and 200 mg BID of sorafenib. On day 8 of run-in the patient will be evaluated for toxicity. In the absence of toxicity, the patient will be escalated to sorafenib 400 mg BID and continue on daily 50 mg of cyclophosphamide, or the patient will be informed to continue on sorafenib 200 mg BID and cyclophosphamide 50 mg QD. Dose escalation procedure will be repeated every 2 weeks until unable to tolerate the study drug, or a maximum of 800 mg BID is reached, or achievement of > 90% inhibition of phosphorylation of PDGFR/Raf axis in PBMC. After "run-in" period, patient begins cycle 1, each cycle will last 28 days. Both cyclophosphamide and sorafenib will be taken orally.; During a run-in period, patient will start taking 50 mg QD of oral cyclophosphamide and 200 mg BID of sorafenib. On day 8 of run-in the patient will be evaluated for toxicity. In the absence of toxicity, the patient will be escalated to sorafenib 400 mg BID and continue on daily 50 mg of cyclophosphamide, or the patient will be informed to continue on sorafenib 200 mg BID and cyclophosphamide 50 mg QD. Dose escalation procedure will be repeated every 2 weeks until unable to tolerate the study drug, or a maximum of 800 mg BID is reached, or achievement of > 90% inhibition of phosphorylation of PDGFR/Raf axis in PBMC. After "run-in" period, patient begins cycle 1, each cycle will last 28 days. Both cyclophosphamide and sorafenib will be taken orally.
Intervention MeSH terms: Cyclophosphamide; Sorafenib
Phase: Phase 2
Study type: Interventional
Primary purpose: Supportive Care
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Neuroendocrine; sorafenib; cyclophosphamide; pharmacodynamic

Summary:

      This is a phase II clinical trial to assess the efficacy of the combination of metronomic
      cyclophosphamide and tailored sorafenib dosing in advanced, progressive NET. NET are highly
      vascular tumors, and high VEGF expression has been correlated with worse clinical and
      pathological characteristics as well as poor prognosis. A novel antiangiogenic approach
      relies on targeting not only the endothelial cells but also rendering them more sensitive to
      VEGFR blockade by achieving pericyte detachment. In this study, the dose of sorafenib will be
      titrated up to a maximum of 800mg BID based on patients' toxicity and on a novel
      pharmacodynamic assay that measures inhibition of molecular target(PDGFR) in patients'
      peripheral blood mononuclear cells. Dual VEGFR targeting is achieved by administering
      sorafenib plus metronomic low dose cyclophosphamide.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically or cytologically confirmed neuroendocrine tumors

          -  Progressive and measurable metastatic disease

          -  Patients must not have disease that is currently amenable to surgery

          -  Life expectancy of greater than 3 months

          -  ECOG performance status ≤2

          -  Patients must have normal organ and marrow function

          -  Negative pregnancy test; agreement to use adequate birth control

        Exclusion Criteria:

          -  Patients receiving chemotherapy or radiotherapy within last 4 weeks

          -  Patients that had received Sorafenib for advanced NET(neuroendocrine tumors) are not
             allowed

          -  Any other investigational agents within 4 weeks of study

          -  Patients with known brain metastases

          -  History of allergic reactions to compounds of similar chemical/biologic composition to
             sorafenib or cyclophosphamide

          -  Concurrent cancer from another primary site requiring treatment within the past 3
             years

          -  Uncontrolled intercurrent illness

          -  Pregnant women and women who are breastfeeding

          -  HIV-positive patients receiving combination anti-retroviral therapy