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Trial record 29 of 827 for:    Advanced | Neuroendocrine Tumors

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

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.

Condition or disease Intervention/treatment Phase
Neuroendocrine Tumors Drug: Sorafenib Drug: Cyclophosphamide Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Intervention Model: Single Group Assignment
Masking: None (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
Study Start Date : January 2008
Actual Primary Completion Date : February 2015
Actual Study Completion Date : February 2015


Arm Intervention/treatment
Experimental: I
Patients will receive sorafenib and cyclophosphamide.
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




Primary Outcome Measures :
  1. 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.


  2. 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).



Secondary Outcome Measures :
  1. 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.

  2. Overall Survival (OS) [ Time Frame: Assessed from start of study treatment until death, assessed up to 7 years. ]
  3. 1-year Survival Rate [ Time Frame: 1 year ]
    Survival rate at 1 year.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00605566


Locations
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Canada, Ontario
Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
University Health Network, Toronto
Investigators
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Principal Investigator: Lillian Siu, MD University Health Network, Toronto

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Responsible Party: University Health Network, Toronto
ClinicalTrials.gov Identifier: NCT00605566     History of Changes
Other Study ID Numbers: SOR-NET-001
First Posted: January 31, 2008    Key Record Dates
Results First Posted: February 19, 2019
Last Update Posted: February 19, 2019
Last Verified: October 2018

Keywords provided by University Health Network, Toronto:
Neuroendocrine
sorafenib
cyclophosphamide
pharmacodynamic

Additional relevant MeSH terms:
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Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Cyclophosphamide
Sorafenib
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Protein Kinase Inhibitors
Enzyme Inhibitors