Imaging of Intravenous (IV) Combidex to Brain, Intra-cerebral Tumors and in Central Nervous System (CNS) Inflammation

• Sponsor: OHSU Knight Cancer Institute (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00659334
• Collaborator: National Institutes of Health (NIH) (NIH), National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
• Enrollment: 116
• Location: 1
• Arms: 7
• Duration (Months): 115
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

Combidex (ferumoxtran-10) is an ultra-small iron oxide particle covered with a sugar coating. It has been evaluated as an MRI contrast agent for use in imaging well perfused organs such as the liver and spleen and for imaging lymph nodes. In this study, Combidex is being used to compare the standard imaging agent, Gadolinium, in imaging brain tumors and the area adjacent to the tumor location. Combidex may provide the ability to better see brain tumors and inflammatory lesions on magnetic resonance imaging (MRI) scans. Combidex may be useful in its ability to cross blood vessels into brain tumors, and because of its size and ability to get into the area next to brain tumors, could assist in the treatment of brain tumors with other drugs in the future.

Condition or Disease	Intervention/Treatment	Phase
Brain Neoplasms	Drug: Ferumoxtran-10 (Combidex); Procedure: Neurosurgery	Phase 2

Detailed Description

Subjects are recruited as patients in one of the neurology, neurosurgery or neuro-oncology clinics at OHSU. There are four groups of the study:

• Subjects receive the combidex infusion only.

• Subjects receive Combidex and undergo a previously schedule neurosurgery.

• Subjects undergo surgery only and provide a sample of their tumor tissue to be used in pathology studies of Combidex.

• Subjects with MS or stroke are invited to participate in receiving Combidex to evaluate the effectiveness of enhancing the area of damage within the brain.

Subjects are deemed eligible for the study and undergo a baseline MRI within 28 days of receiving Combidex. Subjects receiving Combidex are admitted for a half day into the Oregon Clinical & Translational Research Institute(OCTRI). Combidex is infused I.V. over 30 minutes. Subjects are monitored for side effects and are discharged within about 5 hours after the infusion, if no complications have been noted. Subjects return 24 hours after the infusion for a post infusion MRI scan and return again to one of the neurology clinics for one month follow-up. Subjects enrolled in group 2 undergo surgery 1-2 days after the Combidex infusion and also undergo a 24 post infusion MRI and return for one month follow-up. These subjects are also followed closely by the neurosurgical physician during the course of follow-up. Subjects enrolled in group 3 only undergo surgery and agree to have a piece of their tumor resection or biopsy donated for use in the study. Group 4 is the same as group 1, except the patient population includes multiple sclerosis and stroke instead of patients with brain tumors.

Study Design

• Study Type: Interventional
• Actual Enrollment: 116 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Multi-disciplinary Study: MR, Histologic and EM Imaging of Intravenous Superparamagnetic Crystalline Particles (Combidex) to Brain, Intra-cerebral Tumors and in CNS Inflammation
• Study Start Date: Aug 1, 2000
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: Mar 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 Adults with brain tumor to receive Combidex infusion only	Drug: Ferumoxtran-10 (Combidex); 2.6 mg/kg; Other Names: Combidex
Active Comparator: 2 Adults with brain tumors to receive Combidex infusion and neurosurgery	Drug: Ferumoxtran-10 (Combidex); 2.6 mg/kg; Other Names: Combidex ; Procedure: Neurosurgery; neuro-surgical tumor biopsy or resection to assess particle localization. Biopsy (stereotactic, when possible) will take place following the 24 hour post- Combidex MR and within 48 hrs of i.v. Combidex administration. Biopsies will be taken from the tumor, brain around tumor (BAT) and brain distant to tumor and the MR localization and histology will be compared. The tissue will be obtained by either resection or needle frameless stereotactic biopsy.
Other: 3 Adults with brain tumors to receive neurosurgery only (NO Combidex)	Procedure: Neurosurgery; neuro-surgical tumor biopsy or resection to assess particle localization. Biopsy (stereotactic, when possible) will take place following the 24 hour post- Combidex MR and within 48 hrs of i.v. Combidex administration. Biopsies will be taken from the tumor, brain around tumor (BAT) and brain distant to tumor and the MR localization and histology will be compared. The tissue will be obtained by either resection or needle frameless stereotactic biopsy.
Active Comparator: 4 Children with brain tumors to receive Combidex only	Drug: Ferumoxtran-10 (Combidex); 2.6 mg/kg; Other Names: Combidex
Active Comparator: 5 Children with brain tumors to receive Combidex and neurosurgery	Drug: Ferumoxtran-10 (Combidex); 2.6 mg/kg; Other Names: Combidex ; Procedure: Neurosurgery; neuro-surgical tumor biopsy or resection to assess particle localization. Biopsy (stereotactic, when possible) will take place following the 24 hour post- Combidex MR and within 48 hrs of i.v. Combidex administration. Biopsies will be taken from the tumor, brain around tumor (BAT) and brain distant to tumor and the MR localization and histology will be compared. The tissue will be obtained by either resection or needle frameless stereotactic biopsy.
Other: 6 Children with brain tumors to receive neurosurgery only, NO Combidex	Procedure: Neurosurgery; neuro-surgical tumor biopsy or resection to assess particle localization. Biopsy (stereotactic, when possible) will take place following the 24 hour post- Combidex MR and within 48 hrs of i.v. Combidex administration. Biopsies will be taken from the tumor, brain around tumor (BAT) and brain distant to tumor and the MR localization and histology will be compared. The tissue will be obtained by either resection or needle frameless stereotactic biopsy.
Active Comparator: 7 Adults with Inflammatory lesions (stroke or MS) to receive Combidex only	Drug: Ferumoxtran-10 (Combidex); 2.6 mg/kg; Other Names: Combidex

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Experience Optimal Imaging in Adult and Pediatric Brain Tumors to Establish Timing and Sequencing Parameters of Combidex. [24 hours (some patients between 3 and 72 hours) after administration of Combidex]

   Signal intensity change in participants with Pre and 24 hours Post Combidex on T1, T2, T2* MRI sequences will be assessed (some patients undergo scans at 3 and 72 hours in order to assess radiographic changes at these time points). Combidex will be administered in dose 2.6 mg/kg in adults with high and low grade gliomas, metastases, meningiomas, and PNET; and in pediatric patients with astrocytomas grade i-iv, brain stem gliomas, ependymomas, CNS germ cell tumors, and PNET.

Secondary Outcome Measures

1. Assess the Cellular Uptake of Particles in Brain Tumor Patients by Comparing Imaging Results With Histology and Electron Microscopic Examination of Biopsy Tissue [2 years]

2. Compare Combidex Imaging in Brain Tumor Patients, With Other CNS Inflammatory Lesions Such as Multiple Sclerosis and Stroke. [2 years]

3. Compare Pre- and Post-op Gd Enhanced MRI Combidex Enhanced MR Imaging Done Pre-, Intra- and Post-operatively, to Assess the Degree of Resection and Residual Tumor. [2 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Brain tumor or CNS inflammatory lesion including stroke or MS

• 5 yrs old or older

• Able to undergo MRI without general anesthesia

• Agree to be followed for 1 month following infusion of Combidex

• Sign a written informed consent

• If female and of child-bearing potential, be postmenopausal, sterile, or be on birth control for 1 month prior to study

• Must have a pre-treatment MRI within 28 days before study

Exclusion Criteria:

• Clinically significant signs of uncal herniation

• Allergy to study drug, Combidex

• Hepatic insufficiency

• Stage IV or V renal insufficiency

• If female, pregnant or lactating

• Require anesthesia for MRI scanning

• Hemachromatosis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Oregon Health & Science University	Portland	Oregon	United States	97239

Sponsors and Collaborators

• OHSU Knight Cancer Institute
• National Institutes of Health (NIH)
• National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Edward A Neuwelt, MD, Oregon Health and Science University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Edward Neuwelt, Professor, OHSU Knight Cancer Institute
• ClinicalTrials.gov Identifier: NCT00659334
• Other Study ID Numbers: IRB00001127; 5R01NS034608; OHSU-1127
• First Posted: Apr 16, 2008
• Last Update Posted: May 16, 2017
• Last Verified: Apr 1, 2017

• Keywords provided by Edward Neuwelt, Professor, OHSU Knight Cancer Institute: Combidex; Diagnostic imaging
• Additional relevant MeSH terms: Brain Neoplasms; Inflammation

Study Results

Participant Flow

Recruitment Details	Subjects are recruited as patients in one of the neurology, neurosurgery or neuro-oncology clinics at OHSU.
Pre-assignment Detail	There are seven groups in the study. In Groups 1(adults) and 4(pediatric) subjects receive the Combidex infusion only. In Groups 2(adult) and 5(pediatrics) subjects receive Combidex and undergo neurosurgery. In Groups 3(adult) and 6(pediatric) subjects undergo surgery with tissue exam; and in Group 7(adult only) subjects with MS or stroke.

Arm/Group Title	Combidex Only (Group 1)	Combidex and Neurosurgery (Group 2)	Neurosurgery Only (Group 3)	Combidex Only (Group 4)	Combidex and Neurosurgery (Group 5)	Neurosurgery Only (Group 6)	Inflammatory Lesions (Group 7)
Arm/Group Description	Adults with brain tumor to receive Combidex infusion only	Adults with brain tumors to receive Combidex infusion and neurosurgery	Adults with brain tumors to receive neurosurgery only (NO Combidex)	Children with brain tumors to receive Combidex only	Children with brain tumors to receive Combidex and neurosurgery	Children with brain tumors to receive neurosurgery only, NO Combidex	Adults with Inflammatory lesions (stroke or MS) to receive Combidex only
Period Title: Overall Study
STARTED	46	41	5	2	1	0	21
COMPLETED	38	36	5	2	1	0	20
NOT COMPLETED	8	5	0	0	0	0	1

Baseline Characteristics

Arm/Group Title	Combidex Only (Group 1)	Combidex and Neurosurgery (Group 2)	Neurosurgery Only (Group 3)	Combidex Only (Group 4)	Combidex and Neurosurgery (Group 5)	Neurosurgery Only (Group 6)	Inflammatory Lesions (Group 7)	Total
Arm/Group Description	Adults with brain tumor to receive Combidex infusion only	Adults with brain tumors to receive Combidex infusion and neurosurgery	Adults with brain tumors to receive neurosurgery only (NO Combidex)	Children with brain tumors to receive Combidex only	Children with brain tumors to receive Combidex and neurosurgery	Children with brain tumors to receive neurosurgery only, NO Combidex	Adults with Inflammatory lesions (stroke or MS) to receive Combidex only	Total of all reporting groups
Overall Participants	46	41	5	2	1	0	21	116
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	2 100%	1 100%	0 NaN	3 14.3%
Between 18 and 65 years	37 80.4%	35 85.4%	5 100%	0 0%	0 0%	19 Infinity	96 457.1%
>=65 years	9 19.6%	6 14.6%	0 0%	0 0%	0 0%	2 Infinity	17 81%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.3 (13.2)	48.4 (12.8)	45.4 (14.2)	14.7 (1.4)	14.1 (0)	43.0 (15.3)	48.8 (15.1)
Sex: Female, Male (Count of Participants)
Female	21 45.7%	17 41.5%	2 40%	1 50%	1 100%	8 Infinity	50 238.1%
Male	25 54.3%	24 58.5%	3 60%	1 50%	0 0%	13 Infinity	66 314.3%
Region of Enrollment (participants) [Number]
United States	46 100%	41 100%	5 100%	2 100%	1 100%	21 Infinity	116 552.4%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Experience Optimal Imaging in Adult and Pediatric Brain Tumors to Establish Timing and Sequencing Parameters of Combidex.
Description	Signal intensity change in participants with Pre and 24 hours Post Combidex on T1, T2, T2* MRI sequences will be assessed (some patients undergo scans at 3 and 72 hours in order to assess radiographic changes at these time points). Combidex will be administered in dose 2.6 mg/kg in adults with high and low grade gliomas, metastases, meningiomas, and PNET; and in pediatric patients with astrocytomas grade i-iv, brain stem gliomas, ependymomas, CNS germ cell tumors, and PNET.
Time Frame	24 hours (some patients between 3 and 72 hours) after administration of Combidex

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combidex Only (Group 1)	Combidex and Neurosurgery (Group 2)	Neurosurgery Only (Group 3)	Combidex Only (Group 4)	Combidex and Neurosurgery (Group 5)	Neurosurgery Only (Group 6)	Inflammatory Lesions (Group 7)
Arm/Group Description	Adults with brain tumor to receive Combidex infusion only	Adults with brain tumors to receive Combidex infusion and neurosurgery	Adults with brain tumors to receive neurosurgery only (NO Combidex)	Children with brain tumors to receive Combidex only	Children with brain tumors to receive Combidex and neurosurgery	Children with brain tumors to receive neurosurgery only, NO Combidex	Adults with Inflammatory lesions (stroke or MS) to receive Combidex only
Measure Participants	46	41	0	2	1	0	21
Number [Participants]	36 78.3%	35 85.4%	2 40%	1 50%	20 2000%

2. Secondary Outcome

Title	Assess the Cellular Uptake of Particles in Brain Tumor Patients by Comparing Imaging Results With Histology and Electron Microscopic Examination of Biopsy Tissue
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Compare Combidex Imaging in Brain Tumor Patients, With Other CNS Inflammatory Lesions Such as Multiple Sclerosis and Stroke.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Compare Pre- and Post-op Gd Enhanced MRI Combidex Enhanced MR Imaging Done Pre-, Intra- and Post-operatively, to Assess the Degree of Resection and Residual Tumor.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Adverse Event Reporting Description	Other adverse events were collected/assessed, but none affected over 5% of the patient population.
Arm/Group Title	Combidex Only (Group 1)		Combidex and Neurosurgery (Group 2)		Neurosurgery Only (Group 3)		Combidex Only (Group 4)		Combidex and Neurosurgery (Group 5)		Neurosurgery Only (Group 6)		Inflammatory Lesions (Group 7)
Arm/Group Description	Adults with brain tumor to receive Combidex infusion only		Adults with brain tumors to receive Combidex infusion and neurosurgery		Adults with brain tumors to receive neurosurgery only (NO Combidex)		Children with brain tumors to receive Combidex only		Children with brain tumors to receive Combidex and neurosurgery		Children with brain tumors to receive neurosurgery only, NO Combidex		Adults with Inflammatory lesions (stroke or MS) to receive Combidex only
All Cause Mortality
	Combidex Only (Group 1)		Combidex and Neurosurgery (Group 2)		Neurosurgery Only (Group 3)		Combidex Only (Group 4)		Combidex and Neurosurgery (Group 5)		Neurosurgery Only (Group 6)		Inflammatory Lesions (Group 7)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Combidex Only (Group 1)		Combidex and Neurosurgery (Group 2)		Neurosurgery Only (Group 3)		Combidex Only (Group 4)		Combidex and Neurosurgery (Group 5)		Neurosurgery Only (Group 6)		Inflammatory Lesions (Group 7)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/46 (21.7%)		10/41 (24.4%)		2/5 (40%)		1/2 (50%)		0/1 (0%)		0/0 (NaN)		0/21 (0%)
Infections and infestations
Post-Op Infection	1/46 (2.2%)		0/41 (0%)		0/5 (0%)		0/2 (0%)		0/1 (0%)		0/0 (NaN)	0	0/21 (0%)	0
Nervous system disorders
Disease Progression	9/46 (19.6%)		10/41 (24.4%)		2/5 (40%)		0/2 (0%)		0/1 (0%)		0/0 (NaN)	0	0/21 (0%)	0
Cerebellar Infraction	0/46 (0%)		0/41 (0%)		0/5 (0%)		1/2 (50%)		0/1 (0%)		0/0 (NaN)	0	0/21 (0%)	0
Other (Not Including Serious) Adverse Events
	Combidex Only (Group 1)		Combidex and Neurosurgery (Group 2)		Neurosurgery Only (Group 3)		Combidex Only (Group 4)		Combidex and Neurosurgery (Group 5)		Neurosurgery Only (Group 6)		Inflammatory Lesions (Group 7)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/46 (0%)		0/41 (0%)		0/5 (0%)		0/2 (0%)		0/1 (0%)		0/0 (NaN)		0/21 (0%)

Limitations/Caveats

Early trial termination due to study drug Combidex no longer manufactured.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT 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.