Efficacy Study of Sorafenib and Cyclophosphamide to Treat Neuroendocrine Tumors

Neuroendocrine Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00605566
• Other study ID #: SOR-NET-001
• Status: Completed
• Phase: Phase 2
• Start date: January 2008
• Est. completion date: February 2015

Study information

• Verified date: October 2018
• Source: University Health Network, Toronto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: February 2015
• Est. primary completion date: February 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Neuroendocrine Tumors

Intervention

Drug:
• Sorafenib
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.
• 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.

Locations

Country	Name	City	State
Canada	Princess Margaret Hospital	Toronto	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
University Health Network, Toronto

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	Overall Survival (OS)		Assessed from start of study treatment until death, assessed up to 7 years.
Secondary	1-year Survival Rate	Survival rate at 1 year.	1 year