Efficacy Study of Sorafenib and Cyclophosphamide to Treat Neuroendocrine Tumors

Study Overview
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Brief Summary
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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.

Official Title
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Tailored-dose Sorafenib Plus Metronomic Cyclophosphamide in Advanced Neuroendocrine Tumors (NET): a Phase II Clinical Trial Based on Individual Pharmacodynamic Assessment

Conditions
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Neuroendocrine Tumors

Intervention / Treatment
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* Drug: Sorafenib
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: I<br>Patients will receive sorafenib and cyclophosphamide. | Drug: Sorafenib<br>* 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.<br>* Other names: BAY 43-9006;Drug: Cyclophosphamide<br>* 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.<br>* Other names: Cytoxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of Combination Sorafenib Plus Metronomic Cyclophosphamide in Advanced, Progressive NET, as Measured by the Objective Response Rate (ORR). | 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. | Assessed from start of study treatment until death or disease progression, whichever occurs first up to 7 years | 
| Association Between p-Shift Changes and Treatment Efficacy of Individual Dose Adjustment of Sorafenib | 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). | Assessed from start of study treatment until death, assessed up to 7 years. | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuroendocrine, sorafenib, cyclophosphamide, pharmacodynamic