Neuroendocrine Tumors
Conditions
Keywords
Neuroendocrine, sorafenib, cyclophosphamide, pharmacodynamic
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.
Interventions
DRUGSorafenib
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.
DRUGCyclophosphamide
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.
Sponsors
University Health Network, Toronto
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Combination Sorafenib Plus Metronomic Cyclophosphamide in Advanced, Progressive NET, as Measured by the Objective Response Rate (ORR). | 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | 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) | Assessed from start of study treatment until death, assessed up to 7 years. | — |
| 1-year Survival Rate | 1 year | Survival rate at 1 year. |
Countries
Canada
Participant flow
Recruitment details
Patients were recruited from January 2008 to October 2010.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Clinical deterioration | 1 |
| Overall Study | Poor compliance in run-in period | 1 |
Baseline characteristics
| Characteristic | Sorafenib Plus Cyclophosphamide |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants |
| Age, Continuous | 58 years |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 22 / 22 |
| serious Total, serious adverse events | 11 / 22 |
Outcome results
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).
Time frame: Assessed from start of study treatment until death, assessed up to 7 years.
Population: 6 patients experienced a pharmacodynamic pShift change that was classified as positive, 16 experienced a negative pShift.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sorafenib and Cyclophosphamide | Association Between p-Shift Changes and Treatment Efficacy of Individual Dose Adjustment of Sorafenib | PFS in patients with a negative pShift result | 2.8 months |
| Sorafenib and Cyclophosphamide | Association Between p-Shift Changes and Treatment Efficacy of Individual Dose Adjustment of Sorafenib | PFS in patients with a positive pShift result | 14.9 months |
| Sorafenib and Cyclophosphamide | Association Between p-Shift Changes and Treatment Efficacy of Individual Dose Adjustment of Sorafenib | OS for patients with a negative pShift | 6.4 months |
| Sorafenib and Cyclophosphamide | Association Between p-Shift Changes and Treatment Efficacy of Individual Dose Adjustment of Sorafenib | OS for patients with a positive pShift | 21.3 months |
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.
Time frame: Assessed from start of study treatment until death or disease progression, whichever occurs first up to 7 years
Population: 19 out of 22 patients were evaluable for response.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sorafenib and Cyclophosphamide | Efficacy of Combination Sorafenib Plus Metronomic Cyclophosphamide in Advanced, Progressive NET, as Measured by the Objective Response Rate (ORR). | 1 Participants |
Secondary
1-year Survival Rate
Survival rate at 1 year.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib and Cyclophosphamide | 1-year Survival Rate | 45 percentage of participants |
Secondary
Overall Survival (OS)
Time frame: Assessed from start of study treatment until death, assessed up to 7 years.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib and Cyclophosphamide | Overall Survival (OS) | 11.7 months |
Secondary
Progression-free Survival (PFS)
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib and Cyclophosphamide | Progression-free Survival (PFS) | 3 months |