Efficacy Study of Sorafenib and Cyclophosphamide to Treat Neuroendocrine Tumors

• Sponsor: University Health Network, Toronto (Other)
• Overall Status: Completed
• CT.gov ID: NCT00605566
• Collaborator: (none)
• Enrollment: 22
• Location: 1
• Arm: 1
• Duration (Months): 85
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 22 participants
• Allocation: N/A
• 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: Jan 1, 2008
• Actual Primary Completion Date: Feb 1, 2015
• Actual Study Completion Date: Feb 1, 2015

Arms and Interventions

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 Names: 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 Names: Cytoxan

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. Overall Survival (OS) [Assessed from start of study treatment until death, assessed up to 7 years.]

3. 1-year Survival Rate [1 year]

   Survival rate at 1 year.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9

Sponsors and Collaborators

• University Health Network, Toronto

Investigators

• Principal Investigator: Lillian Siu, MD, University Health Network, Toronto

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University Health Network, Toronto
• ClinicalTrials.gov Identifier: NCT00605566
• Other Study ID Numbers: SOR-NET-001
• First Posted: Jan 31, 2008
• Last Update Posted: Feb 19, 2019
• Last Verified: Oct 1, 2018

• Keywords provided by University Health Network, Toronto: Neuroendocrine; sorafenib; cyclophosphamide; pharmacodynamic
• Additional relevant MeSH terms: Neuroendocrine Tumors; Cyclophosphamide; Sorafenib

Study Results

Participant Flow

Recruitment Details	Patients were recruited from January 2008 to October 2010.

Arm/Group Title	Sorafenib and Cyclophosphamide
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.
Period Title: Overall Study
STARTED	22
COMPLETED	19
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Sorafenib Plus Cyclophosphamide
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 Participants	22
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	17 77.3%
>=65 years	5 22.7%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	58
Sex: Female, Male (Count of Participants)
Female	10 45.5%
Male	12 54.5%

Outcome Measures

1. Primary Outcome

Title	Efficacy of Combination Sorafenib Plus Metronomic Cyclophosphamide in Advanced, Progressive NET, as Measured by the Objective Response Rate (ORR).
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

Outcome Measure Data

Analysis Population Description

19 out of 22 patients were evaluable for response.

Arm/Group Title	Sorafenib and Cyclophosphamide
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.
Measure Participants	19
Count of Participants [Participants]	1 4.5%

2. Primary Outcome

Title	Association Between p-Shift Changes and Treatment Efficacy of Individual Dose Adjustment of Sorafenib
Description	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.

Outcome Measure Data

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
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.
Measure Participants	22
PFS in patients with a negative pShift result	2.8
PFS in patients with a positive pShift result	14.9
OS for patients with a negative pShift	6.4
OS for patients with a positive pShift	21.3

3. Secondary Outcome

Title	Progression-free Survival (PFS)
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sorafenib and Cyclophosphamide
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.
Measure Participants	22
Median (95% Confidence Interval) [months]	3

4. Secondary Outcome

Title	Overall Survival (OS)
Time Frame	Assessed from start of study treatment until death, assessed up to 7 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sorafenib and Cyclophosphamide
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.
Measure Participants	22
Median (95% Confidence Interval) [months]	11.7

5. Secondary Outcome

Title	1-year Survival Rate
Description	Survival rate at 1 year.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sorafenib and Cyclophosphamide
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.
Measure Participants	22
Number [percentage of participants]	45 204.5%

Adverse Events

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.
Arm/Group Title	Sorafenib Plus Cyclophosphamide
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 (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Sorafenib Plus Cyclophosphamide
	Affected / at Risk (%)	# Events
Total	11/22 (50%)
Gastrointestinal disorders
Ileal perforation	1/22 (4.5%)	1
Abdominal Pain	2/22 (9.1%)	2
Dyspepsia	1/22 (4.5%)	1
Diarrhea	1/22 (4.5%)	1
Small intestinal obstruction	1/22 (4.5%)	1
General disorders
Disease progression	1/22 (4.5%)	1
Fever	1/22 (4.5%)	1
Infections and infestations
Infection	1/22 (4.5%)	1
Investigations
Weight Gain	1/22 (4.5%)	1
Bilirubin increased	1/22 (4.5%)	1
Lipase increased	2/22 (9.1%)	2
Amylase increased	1/22 (4.5%)	1
Musculoskeletal and connective tissue disorders
Neck pain	1/22 (4.5%)	1
Renal and urinary disorders
Protein Urine Positive	1/22 (4.5%)	1
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome	1/22 (4.5%)	1
Vascular disorders
Flushing	1/22 (4.5%)	1
Other (Not Including Serious) Adverse Events
	Sorafenib Plus Cyclophosphamide
	Affected / at Risk (%)	# Events
Total	22/22 (100%)
Gastrointestinal disorders
Diarrhoea	12/22 (54.5%)
Nausea	8/22 (36.4%)
Vomiting	5/22 (22.7%)
General disorders
Fatigue	9/22 (40.9%)
Investigations
Lymphopenia	7/22 (31.8%)
Weight loss	6/22 (27.3%)
Aspartate aminotransferase elevation	6/22 (27.3%)
Thrombocytopenia	3/22 (13.6%)
Lipase elevation	6/22 (27.3%)
Amylase elevation	5/22 (22.7%)
Alanine aminotransferase elevation	3/22 (13.6%)
Metabolism and nutrition disorders
Hypophosphatemia	11/22 (50%)
Hypocalcemia	3/22 (13.6%)
Nervous system disorders
Dysgeusia	5/22 (22.7%)
Peripheral sensory neuropathy	1/22 (4.5%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome	10/22 (45.5%)
Alopecia	4/22 (18.2%)
Rash	9/22 (40.9%)
Vascular disorders
Hypertension	3/22 (13.6%)

Limitations/Caveats

[Not Specified]

More Information

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.