Efficacy Study of Sorafenib and Cyclophosphamide to Treat Neuroendocrine Tumors

Phase 2

Completed

Brief 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.

Recruitment & Eligibility

Inclusion Criteria

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

Arm && Interventions

Group	Intervention	Description
I	Sorafenib	Patients will receive sorafenib and cyclophosphamide.
I	Cyclophosphamide	Patients will receive sorafenib and cyclophosphamide.

Primary Outcome Measures

Name	Time	Method
Efficacy of Combination Sorafenib Plus Metronomic Cyclophosphamide in Advanced, Progressive NET, as Measured by the Objective Response Rate (ORR).	Assessed from start of study treatment until death or disease progression, whichever occurs first up to 7 years	Objective response (complete and partial) evaluated using RECIST criteria. Complete response (CR): disappearance of all clinical and radiological evidence of tumour (both target and non-target). Partial response (PR): at least a 30% decrease in the sum of longest diameter of target lesions.
Association Between p-Shift Changes and Treatment Efficacy of Individual Dose Adjustment of Sorafenib	Assessed from start of study treatment until death, assessed up to 7 years.	A phosphoshift (pShift) flow cytometry-based test that measures RAF signal transduction capacity in peripheral blood cells was used in order to predict clinical course and/or guide individual dose-titration. Positive pShift values denote stimulation of RAF signal transduction, whereas negative pShift values denote inhibition of RAF signal transduction as measured by flow-cytometry. Associations between pShift changes and treatment efficacy were measured using progression-free survival (PFS) and overall survival (OS).

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS)	Assessed from start of study treatment until death or disease progression, whichever occurs first up to 7 years	Progressive disease (PD): at least a 20% increase in the sum of the longest diameter of measured lesions.
1-year Survival Rate	1 year	Survival rate at 1 year.
Overall Survival (OS)	Assessed from start of study treatment until death, assessed up to 7 years.