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Completed

NCT Number: NCT00605566

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.

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Key information

Conditions

Neuroendocrine Tumors Neoplasms Neoplasms by Histologic Type Neoplasms, Germ Cell and Embryonal Neoplasms, Nerve Tissue Neuroectodermal Tumors

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Princess Margaret Hospital

Toronto, Ontario, M5G 2M9, Canada

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Sorafenib

Drug

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 names: BAY 43-9006

Cyclophosphamide

Drug

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 names: Cytoxan

Primary outcomes

  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 outcomes

  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.

Sponsors and collaborators

Lead sponsor

University Health Network, Toronto

Other

Registry information

Official study title

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

Important dates

Study start
2008
Primary completion
2015
Study completion
2015
First posted
Jan 31, 2008
Registry last updated
Feb 19, 2019

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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