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Efficacy Study of Sorafenib and Cyclophosphamide to Treat Neuroendocrine Tumors

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ClinicalTrials.gov Identifier: NCT00605566
Recruitment Status : Completed
First Posted : January 31, 2008
Results First Posted : February 19, 2019
Last Update Posted : February 19, 2019
Sponsor:
Information provided by (Responsible Party):
University Health Network, Toronto

Tracking Information
First Submitted Date  ICMJE January 18, 2008
First Posted Date  ICMJE January 31, 2008
Results First Submitted Date  ICMJE October 30, 2017
Results First Posted Date  ICMJE February 19, 2019
Last Update Posted Date February 19, 2019
Study Start Date  ICMJE January 2008
Actual Primary Completion Date February 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 9, 2018)
  • Efficacy of Combination Sorafenib Plus Metronomic Cyclophosphamide in Advanced, Progressive NET, as Measured by the Objective Response Rate (ORR). [ Time Frame: 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 [ Time Frame: 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).
Original Primary Outcome Measures  ICMJE
 (submitted: January 18, 2008)
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 12 weeks ]
Change History Complete list of historical versions of study NCT00605566 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 9, 2018)
  • Progression-free Survival (PFS) [ Time Frame: 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.
  • Overall Survival (OS) [ Time Frame: Assessed from start of study treatment until death, assessed up to 7 years. ]
  • 1-year Survival Rate [ Time Frame: 1 year ]
    Survival rate at 1 year.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 18, 2008)
To assess the toxicity, time-to-progression (TTP), overall survival (OS), and 1 year survival rate. [ Time Frame: One year ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy Study of Sorafenib and Cyclophosphamide to Treat Neuroendocrine Tumors
Official Title  ICMJE Tailored-dose Sorafenib Plus Metronomic Cyclophosphamide in Advanced Neuroendocrine Tumors (NET): a Phase II Clinical Trial Based on Individual Pharmacodynamic Assessment
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Supportive Care
Condition  ICMJE Neuroendocrine Tumors
Intervention  ICMJE
  • 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.
    Other Name: BAY 43-9006
  • Drug: 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.
    Other Name: Cytoxan
Study Arms  ICMJE Experimental: I
Patients will receive sorafenib and cyclophosphamide.
Interventions:
  • Drug: Sorafenib
  • Drug: Cyclophosphamide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 14, 2016)
22
Original Estimated Enrollment  ICMJE
 (submitted: January 18, 2008)
41
Actual Study Completion Date  ICMJE February 2015
Actual Primary Completion Date February 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00605566
Other Study ID Numbers  ICMJE SOR-NET-001
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University Health Network, Toronto
Study Sponsor  ICMJE University Health Network, Toronto
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Lillian Siu, MD University Health Network, Toronto
PRS Account University Health Network, Toronto
Verification Date October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP