Efficacy Study of Sorafenib and Cyclophosphamide to Treat Neuroendocrine Tumors
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.
|Study Design:||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Supportive Care
|Official Title:||Tailored-dose Sorafenib Plus Metronomic Cyclophosphamide in Advanced Neuroendocrine Tumors (NET): a Phase II Clinical Trial Based on Individual Pharmacodynamic Assessment|
- To determine the efficacy of combination sorafenib plus metronomic cyclophosphamide in advanced, progressive NET, as measured by the objective response rate (ORR), and to assess the feasibility of the individual dose adjustment of sorafenib. [ Time Frame: Every 8 weeks ] [ Designated as safety issue: No ]
- To assess the toxicity, time-to-progression (TTP), overall survival (OS), and 1 year survival rate. [ Time Frame: One year ] [ Designated as safety issue: Yes ]
|Study Start Date:||January 2008|
|Estimated Study Completion Date:||May 2013|
|Primary Completion Date:||March 2011 (Final data collection date for primary outcome measure)|
Patients will receive sorafenib and cyclophosphamide.
Drug: sorafenib and cyclophosphamide
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.
|Princess Margaret Hospital|
|Toronto, Ontario, Canada, M5G 2M9|
|Principal Investigator:||Lillian Siu, MD||University Health Network, Toronto|