Back to resultsEfficacy Study of Sorafenib and Cyclophosphamide to Treat Neuroendocrine Tumors
Primary Purpose
Neuroendocrine Tumors
Status
Completed
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Sorafenib
Cyclophosphamide
Sponsored by
About this trial
This is an interventional supportive care trial for Neuroendocrine Tumors focused on measuring Neuroendocrine, sorafenib, cyclophosphamide, pharmacodynamic
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
Sites / Locations
- Princess Margaret Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
I
Arm Description
Patients will receive sorafenib and cyclophosphamide.
Outcomes
Primary Outcome Measures
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.
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).
Secondary Outcome Measures
Progression-free Survival (PFS)
Progressive disease (PD): at least a 20% increase in the sum of the longest diameter of measured lesions.
Overall Survival (OS)
1-year Survival Rate
Survival rate at 1 year.
Full Information
NCT ID
NCT00605566
First Posted
January 18, 2008
Last Updated
October 9, 2018
Sponsor
University Health Network, Toronto
1. Study Identification
Unique Protocol Identification Number
NCT00605566
Brief Title
Efficacy Study of Sorafenib and Cyclophosphamide to Treat Neuroendocrine Tumors
Official Title
Tailored-dose Sorafenib Plus Metronomic Cyclophosphamide in Advanced Neuroendocrine Tumors (NET): a Phase II Clinical Trial Based on Individual Pharmacodynamic Assessment
Study Type
Interventional
2. Study Status
Record Verification Date
October 2018
Overall Recruitment Status
Completed
Study Start Date
January 2008 (undefined)
Primary Completion Date
February 2015 (Actual)
Study Completion Date
February 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Health Network, Toronto
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuroendocrine Tumors
Keywords
Neuroendocrine, sorafenib, cyclophosphamide, pharmacodynamic
7. Study Design
Primary Purpose
Supportive Care
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
22 (Actual)
8. Arms, Groups, and Interventions
Arm Title
I
Arm Type
Experimental
Arm Description
Patients will receive sorafenib and cyclophosphamide.
Intervention Type
Drug
Intervention Name(s)
Sorafenib
Other Intervention Name(s)
BAY 43-9006
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.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan
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.
Primary Outcome Measure Information:
Title
Efficacy of Combination Sorafenib Plus Metronomic Cyclophosphamide in Advanced, Progressive NET, as Measured by the Objective Response Rate (ORR).
Description
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.
Time Frame
Assessed from start of study treatment until death or disease progression, whichever occurs first up to 7 years
Title
Association Between p-Shift Changes and Treatment Efficacy of Individual Dose Adjustment of Sorafenib
Description
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).
Time Frame
Assessed from start of study treatment until death, assessed up to 7 years.
Secondary Outcome Measure Information:
Title
Progression-free Survival (PFS)
Description
Progressive disease (PD): at least a 20% increase in the sum of the longest diameter of measured lesions.
Time Frame
Assessed from start of study treatment until death or disease progression, whichever occurs first up to 7 years
Title
Overall Survival (OS)
Time Frame
Assessed from start of study treatment until death, assessed up to 7 years.
Title
1-year Survival Rate
Description
Survival rate at 1 year.
Time Frame
1 year
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lillian Siu, MD
Organizational Affiliation
University Health Network, Toronto
Official's Role
Principal Investigator
Facility Information:
Facility Name
Princess Margaret Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada
12. IPD Sharing Statement
Learn more about this trial
Efficacy Study of Sorafenib and Cyclophosphamide to Treat Neuroendocrine Tumors
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