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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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| I | Experimental | Patients will receive sorafenib and cyclophosphamide. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Overall Survival (OS) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Lillian Siu, MD | University Health Network, Toronto | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Princess Margaret Hospital | Toronto | Ontario | M5G 2M9 | Canada |
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Patients were recruited from January 2008 to October 2010.
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| ID | Title | Description |
|---|---|---|
| FG000 | Sorafenib and Cyclophosphamide | Patients will receive sorafenib and cyclophosphamide. sorafenib and 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Sorafenib Plus Cyclophosphamide | Patients will receive sorafenib and cyclophosphamide. sorafenib and 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 19 out of 22 patients were evaluable for response. | Posted | Count of Participants | Participants | No | Assessed from start of study treatment until death or disease progression, whichever occurs first up to 7 years |
|
Adverse event data were collected over a total of 160 treatment cycles (1 cycle = 28 days) for all study participants, for as long as 7 years.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Sorafenib Plus Cyclophosphamide | Patients will receive sorafenib and cyclophosphamide. sorafenib and 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Ileal perforation | Gastrointestinal disorders |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Palmar-plantar erythrodysesthesia syndrome | Skin and subcutaneous tissue disorders |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Lillian Siu | Princess Margaret Cancer Centre | lillian.siu@uhn.ca |
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| ID | Term |
|---|---|
| D018358 | Neuroendocrine Tumors |
| ID | Term |
|---|---|
| D017599 | Neuroectodermal Tumors |
| D009373 | Neoplasms, Germ Cell and Embryonal |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| D000077157 | Sorafenib |
| D003520 | Cyclophosphamide |
| ID | Term |
|---|---|
| D010671 | Phenylurea Compounds |
| D014508 | Urea |
| D000577 | Amides |
| D009930 | Organic Chemicals |
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|
|
| 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. |
|
|
| Assessed from start of study treatment until death, assessed up to 7 years. |
| 1-year Survival Rate | Survival rate at 1 year. | 1 year |
| Participants |
|
| Age, Continuous | Median | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
|
|
| 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). | 6 patients experienced a pharmacodynamic pShift change that was classified as positive, 16 experienced a negative pShift. | Posted | Median | 95% Confidence Interval | months | 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. | Posted | Median | 95% Confidence Interval | months | Assessed from start of study treatment until death or disease progression, whichever occurs first up to 7 years |
|
|
|
| Secondary | Overall Survival (OS) | Posted | Median | 95% Confidence Interval | months | Assessed from start of study treatment until death, assessed up to 7 years. |
|
|
|
| Secondary | 1-year Survival Rate | Survival rate at 1 year. | Posted | Number | percentage of participants | 1 year |
|
|
|
| 11 |
| 22 |
| 22 |
| 22 |
| Abdominal Pain | Gastrointestinal disorders |
|
| Flushing | Vascular disorders |
|
| Palmar-plantar erythrodysesthesia syndrome | Skin and subcutaneous tissue disorders |
|
| Protein Urine Positive | Renal and urinary disorders |
|
| Dyspepsia | Gastrointestinal disorders |
|
| Weight Gain | Investigations |
|
| Disease progression | General disorders |
|
| Bilirubin increased | Investigations |
|
| Lipase increased | Investigations |
|
| Amylase increased | Investigations |
|
| Fever | General disorders |
|
| Diarrhea | Gastrointestinal disorders |
|
| Infection | Infections and infestations |
|
| Neck pain | Musculoskeletal and connective tissue disorders |
|
| Small intestinal obstruction | Gastrointestinal disorders |
|
| Dysgeusia | Nervous system disorders |
|
| Hypertension | Vascular disorders |
|
| Fatigue | General disorders |
|
| Diarrhoea | Gastrointestinal disorders |
|
| Alopecia | Skin and subcutaneous tissue disorders |
|
| Hypophosphatemia | Metabolism and nutrition disorders |
|
| Rash | Skin and subcutaneous tissue disorders |
|
| Lymphopenia | Investigations |
|
| Weight loss | Investigations |
|
| Aspartate aminotransferase elevation | Investigations |
|
| Nausea | Gastrointestinal disorders |
|
| Thrombocytopenia | Investigations |
|
| Lipase elevation | Investigations |
|
| Peripheral sensory neuropathy | Nervous system disorders |
|
| Amylase elevation | Investigations |
|
| Vomiting | Gastrointestinal disorders |
|
| Alanine aminotransferase elevation | Investigations |
|
| Hypocalcemia | Metabolism and nutrition disorders |
|
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| D009380 | Neoplasms, Nerve Tissue |
| D001555 |
| Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009536 | Niacinamide |
| D009539 | Nicotinic Acids |
| D000147 | Acids, Heterocyclic |
| D006571 | Heterocyclic Compounds |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| D063088 | Phosphoramides |
| D009943 | Organophosphorus Compounds |
|
| OS for patients with a negative pShift |
|
|
| OS for patients with a positive pShift |
|
|