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Trial record 77 of 2710 for:    Neoplasms, Germ Cell and Embryonal | Neuroendocrine Tumors

Efficacy Study of Sorafenib and Cyclophosphamide to Treat Neuroendocrine Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
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

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Supportive Care
Condition Neuroendocrine Tumors
Interventions Drug: Sorafenib
Drug: Cyclophosphamide
Enrollment 22
Recruitment Details Patients were recruited from January 2008 to October 2010.
Pre-assignment Details  
Arm/Group Title Sorafenib and Cyclophosphamide
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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.

Period Title: Overall Study
Started 22
Completed 19
Not Completed 3
Reason Not Completed
Adverse Event             1
Clinical deterioration             1
Poor compliance in run-in period             1
Arm/Group Title Sorafenib Plus Cyclophosphamide
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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.

Overall Number of Baseline Participants 22
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants
<=18 years
0
   0.0%
Between 18 and 65 years
17
  77.3%
>=65 years
5
  22.7%
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 22 participants
58
(32 to 80)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants
Female
10
  45.5%
Male
12
  54.5%
1.Primary Outcome
Title Efficacy of Combination Sorafenib Plus Metronomic Cyclophosphamide in Advanced, Progressive NET, as Measured by the Objective Response Rate (ORR).
Hide Description

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
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Hide Analysis Population Description
19 out of 22 patients were evaluable for response.
Arm/Group Title Sorafenib and Cyclophosphamide
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 19
Measure Type: Count of Participants
Unit of Measure: Participants
1
2.Primary Outcome
Title Association Between p-Shift Changes and Treatment Efficacy of Individual Dose Adjustment of Sorafenib
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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.
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Hide Analysis Population Description
6 patients experienced a pharmacodynamic pShift change that was classified as positive, 16 experienced a negative pShift.
Arm/Group Title Sorafenib and Cyclophosphamide
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 22
Median (95% Confidence Interval)
Unit of Measure: months
PFS in patients with a negative pShift result Number Analyzed 16 participants
2.8
(1.8 to 6.7)
PFS in patients with a positive pShift result Number Analyzed 6 participants
14.9 [1] 
(3 to NA)
OS for patients with a negative pShift Number Analyzed 16 participants
6.4
(2.8 to 6.4)
OS for patients with a positive pShift Number Analyzed 6 participants
21.3 [1] 
(7.9 to NA)
[1]
Not reached
3.Secondary Outcome
Title Progression-free Survival (PFS)
Hide Description 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
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Hide Analysis Population Description
[Not Specified]
Arm/Group Title Sorafenib and Cyclophosphamide
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 22
Median (95% Confidence Interval)
Unit of Measure: months
3
(2 to 10.7)
4.Secondary Outcome
Title Overall Survival (OS)
Hide Description [Not Specified]
Time Frame Assessed from start of study treatment until death, assessed up to 7 years.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Sorafenib and Cyclophosphamide
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 22
Median (95% Confidence Interval)
Unit of Measure: months
11.7 [1] 
(4.3 to NA)
[1]
Not reached
5.Secondary Outcome
Title 1-year Survival Rate
Hide Description Survival rate at 1 year.
Time Frame 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Sorafenib and Cyclophosphamide
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 22
Measure Type: Number
Unit of Measure: percentage of participants
45
Time Frame 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.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Sorafenib Plus Cyclophosphamide
Hide Arm/Group Description

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.

All-Cause Mortality
Sorafenib Plus Cyclophosphamide
Affected / at Risk (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Sorafenib Plus Cyclophosphamide
Affected / at Risk (%) # Events
Total   11/22 (50.00%)    
Gastrointestinal disorders   
Ileal perforation  1/22 (4.55%)  1
Abdominal Pain  2/22 (9.09%)  2
Dyspepsia  1/22 (4.55%)  1
Diarrhea  1/22 (4.55%)  1
Small intestinal obstruction  1/22 (4.55%)  1
General disorders   
Disease progression  1/22 (4.55%)  1
Fever  1/22 (4.55%)  1
Infections and infestations   
Infection  1/22 (4.55%)  1
Investigations   
Weight Gain  1/22 (4.55%)  1
Bilirubin increased  1/22 (4.55%)  1
Lipase increased  2/22 (9.09%)  2
Amylase increased  1/22 (4.55%)  1
Musculoskeletal and connective tissue disorders   
Neck pain  1/22 (4.55%)  1
Renal and urinary disorders   
Protein Urine Positive  1/22 (4.55%)  1
Skin and subcutaneous tissue disorders   
Palmar-plantar erythrodysesthesia syndrome  1/22 (4.55%)  1
Vascular disorders   
Flushing  1/22 (4.55%)  1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Sorafenib Plus Cyclophosphamide
Affected / at Risk (%) # Events
Total   22/22 (100.00%)    
Gastrointestinal disorders   
Diarrhoea  12/22 (54.55%) 
Nausea  8/22 (36.36%) 
Vomiting  5/22 (22.73%) 
General disorders   
Fatigue  9/22 (40.91%) 
Investigations   
Lymphopenia  7/22 (31.82%) 
Weight loss  6/22 (27.27%) 
Aspartate aminotransferase elevation  6/22 (27.27%) 
Thrombocytopenia  3/22 (13.64%) 
Lipase elevation  6/22 (27.27%) 
Amylase elevation  5/22 (22.73%) 
Alanine aminotransferase elevation  3/22 (13.64%) 
Metabolism and nutrition disorders   
Hypophosphatemia  11/22 (50.00%) 
Hypocalcemia  3/22 (13.64%) 
Nervous system disorders   
Dysgeusia  5/22 (22.73%) 
Peripheral sensory neuropathy  1/22 (4.55%) 
Skin and subcutaneous tissue disorders   
Palmar-plantar erythrodysesthesia syndrome  10/22 (45.45%) 
Alopecia  4/22 (18.18%) 
Rash  9/22 (40.91%) 
Vascular disorders   
Hypertension  3/22 (13.64%) 
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Dr. Lillian Siu
Organization: Princess Margaret Cancer Centre
Responsible Party: University Health Network, Toronto
ClinicalTrials.gov Identifier: NCT00605566     History of Changes
Other Study ID Numbers: SOR-NET-001
First Submitted: January 18, 2008
First Posted: January 31, 2008
Results First Submitted: October 30, 2017
Results First Posted: February 19, 2019
Last Update Posted: February 19, 2019