The Role of Bevacizumab in the Treatment of Radiation Necrosis in Children With Central Nervous System Tumors

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01201850
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 7
• Location: 1
• Arm: 1
• Actual Duration (Months): 73.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study is being done to learn about the safety of the study drug bevacizumab(Avastin®), when used to treat radiation necrosis.

The primary objective of this study is to test the feasibility of treating Central Nervous System (CNS) tumor patients suffering from radiation necrosis with bevacizumab every 2 weeks.

The secondary objectives of this study are:

• To evaluate improvement in neurologic symptoms associated with bevacizumab as assessed by clinical evaluation;

• To investigate the neuro-imaging changes in radiation necrosis associated edema, including Mass Resonance (MR) spectroscopy;

• To evaluate changes in corticosteroid use in patients with radiation necrosis following treatment with bevacizumab;

• To evaluate changes in quality of life.

Condition or Disease	Intervention/Treatment	Phase
Radiation Necrosis	Drug: Bevacizumab (Avastin®)	N/A

Detailed Description

Treatment Plan:

For patient consented and enrolled on study, bevacizumab will be administered at a dose of 10 mg/kg IV every 2 weeks for a total of 6 doses (3 doses/cycle).

Patients are expected to receive at least 1 cycle (6 weeks) of study treatment unless an unacceptable drug reaction occurs. Patients will receive a second cycle of treatment as long as treatment is tolerated. Response assessment will be performed every 6 weeks (three doses/cycle of study drug) including clinical and radiological assessment. Secondary measures including documentation of total equivalent steroid dose, length of time on steroids, and quality of life using the modified McMaster Health Instrument scale will also be collected while on treatment and 30 days after finishing treatment.

Safety will be assessed by routine physical and laboratory evaluations. Adverse events will be recorded and the severity graded according to the NCI Common Terminology Criteria for Adverse Events (version 4.0).

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Role of Bevacizumab in the Treatment of Radiation Necrosis in Children With Central Nervous System Tumors
• Actual Study Start Date: Jun 28, 2010
• Actual Primary Completion Date: Aug 4, 2016
• Actual Study Completion Date: Aug 4, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bevacizumab (Avastin®) Once enrolled on study, patients will be treated with bevacizumab (10mg/kg) intravenously (i.v.) every 2 weeks for a total of 6 doses.	Drug: Bevacizumab (Avastin®); Once enrolled on study, patients will be treated with bevacizumab (10mg/kg) intravenously (i.v.) every 2 weeks for a total of 6 doses. An MRI will be done after the first cycle (3 doses/ 6weeks) and then again at the end of therapy.

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Received at Least 5 of the 6 Scheduled Doses of Bevacizumab [13 weeks]

   This pilot study was designed to evaluate the feasibility of treating pediatric patients with CNS radiation necrosis with bevacizumab. Patients enrolled on study were assessed for number of doses of bevacizumab that they received while on study. Participants who successfully received at least 5 of the 6 planned doses of bevacizumab (IV every 2 weeks) without significant events were determined to have met the outcome measure.

Secondary Outcome Measures

1. Neurologic Status With Bevacizumab Treatment [13 weeks]

   Outcome 1: Monitor overall neurologic status and symptoms before, during and 1 month following treatment with bevacizumab.

2. Corticosteroid Usage With Bevacixumab Treatment [13 weeks]

   Outcome 2: Dose and duration of corticosteroid use prior to, during, and up to 1 month following bevacizumab treatment will also be collected and evaluated.

3. Changes in Quality of Life With Bevacizumab Treatment [13 weeks]

   Outcome 3: To evaluate changes in quality of life before and after treatment with bevacizumab Modified McMasters Scale was used. Minimum score: 1 Maximum score 35. Higher score indicates worse quality of life.

4. Number of Patients With Changes in Neuro-Imaging With Bevacizumab Treatment [13 weeks]

   Outcome 4: To investigate the neuro-imaging changes in radiation necrosis associated edema, including Mass Resonance (MR) spectroscopy; MRIs (including FLAIR sequences and contrast enhanced images) were evaluated for changes in the radiation necrosis imaging characteristics by a pediatric radiologist. Decreases in gadolinium enhancement, FLAIR signal were considered changes consistent with decreased edema. Tumor size was also evaluated, with a decrease in tumor size indicating decreased edema/improved radiation necrosis

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 25 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age ≥ 1 and < 25 years of age at diagnosis

• Interval from radiation therapy at least 4 weeks and no more than 1 year

• Neurologic deterioration (long tract signs, cranial nerve signs or ataxia) consistent with radiation necrosis

• MRI imaging with findings consistent with radiation necrosis as confirmed by the study radiologist

• Craniotomy or intracranial biopsy site must be adequately healed, free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of study entry

• More than 28 days elapsed from the last surgical procedure (including biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity)

• Lansky or Karnofsky performance > 40%

• Patients may be on steroids at study entry

• Adequate organ function defined as:

• Peripheral absolute neutrophil (ANC) >/= 1000/units/Liter(uL)

• Platelet count >/= 50,000/uL

• Hemoglobin >/= 9.0 gm/dL (transfusion permitted)

• Adequate Coagulation function defined as:

• Prothrombin Time (PT)/activated Partial Thromboplastin Time (aPTT) </= 1.5x institutional upper limit of normal (ULN) for age;

• Adequate Renal Function defined as:

• Serum creatinine </= 1.5x institutional upper limit of normal (ULN) for age. If the serum creatinine is above these values, the calculated creatinine clearance or radioisotope Glomerular Filtration Rate (GFR) must be >/= 60 mL/min/1.73m2;

• Adequate Hepatic Function defined as:

• Total bilirubin </= 1.5x institutional upper limit of normal (ULN);

• Alanine Amniotransferase (ALT) and Aspartate Aminotransferase(AST) </= 2.5x ULN for institution;Serum albumin </= 2.0 g/dL;

• QT corrected (QTc) interval within normal range for age;

• Adequate Pulmonary Function defined as:

• Room air oxygen saturation of >90% at altitude > 5000 feet, or >93% < 5000 feet

• Chemotherapy: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy prior to entering study. Three (3) weeks must have elapsed since the administration of prior chemotherapy.

• Biologic agents: At least 14 days must have elapsed since the completion of therapy with a monoclonal antibody

• Stem cell transplant: patients who have undergone prior stem cell transplant will not be excluded from study entry as long as adequate marrow reserve is demonstrated (refer to hematologic parameters).

• For females of childbearing potential, a negative serum pregnancy test must be documented prior to enrollment

• Patients who enter this study and their sexual partners who are of childbearing potential must agree to use an effective form of contraception throughout participation in this study

• Written informed consent and assent as required by institutional guidelines

Exclusion Criteria:

1. Disease-Specific Exclusions

•Evidence of recent (less than 2 weeks) hemorrhage on postoperative MRI of the brain. However, patients with clinically asymptomatic presence of hemosiderin, resolving hemorrhagic changes related to surgery, and presence of punctate hemorrhage in the tumour are permitted entry into the study.

1. General Medical Exclusions

• Subjects meeting any of the following criteria are ineligible for study entry:

• Inability to comply with study and/or follow-up procedures

• Life expectancy of less than 12 weeks

• Patients who have had chemotherapy within three (3) weeks or radiation within four (4) weeks. Patients may not receive additional chemotherapeutic agents while on this study.

• Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study

• Active second malignancy, other than superficial basal cell and superficial squamous (skin) cell, or carcinoma in situ of the cervix within last five years.

1. Bevacizumab-Specific Exclusions

• Inadequately controlled hypertension (defined as above the normal published range for age and height)

• Prior history of hypertensive crisis or hypertensive encephalopathy

• New York Heart Association (NYHA) Grade II or greater congestive heart failure

• History of myocardial infarction or unstable angina within 12 months prior to Day 1

• No history of stroke or transient ischemic attack

• Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1; History of hemoptysis (greater than or equal to 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1

• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study

• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1

• History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1

• Serious, non-healing wound, active ulcer, or unhealed bone fracture

• Proteinuria as demonstrated by a Urine Protein Creatinine (UPC) ratio greater than or equal to 1.0 at screening

• Known hypersensitivity to any component of bevacizumab

• Pregnancy (positive pregnancy test) or lactation. Use of effective means of contraception (men and women) in subjects of child-bearing potential

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Colorado	Aurora	Colorado	United States	80045

Sponsors and Collaborators

• University of Colorado, Denver
• Genentech, Inc.

Investigators

• Principal Investigator: Margaret Macy, MD, Children's Hospital Colorado

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT01201850
• Other Study ID Numbers: 10-0418.cc
• First Posted: Sep 15, 2010
• Last Update Posted: May 19, 2021
• Last Verified: Apr 1, 2021

• Keywords provided by University of Colorado, Denver: radiation necrosis; Bevacizumab (Avastin®); Central Nervous System Tumors
• Additional relevant MeSH terms: Nervous System Neoplasms; Central Nervous System Neoplasms; Necrosis; Bevacizumab

Study Results

Participant Flow

Arm/Group Title	Bevacizumab (Avastin®)
Arm/Group Description	Once enrolled, patients were treated with bevacizumab (10mg/kg) intravenously (i.v.) every 2 weeks for a total of 6 doses. Bevacizumab (Avastin®): bevacizumab (10mg/kg) intravenously (i.v.) every 2 weeks for a total of 6 doses.
Period Title: Overall Study
STARTED	7
COMPLETED	3
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Bevacizumab (Avastin®)
Arm/Group Description	Once enrolled, patients were treated with bevacizumab (10mg/kg) intravenously (i.v.) every 2 weeks for a total of 6 doses. Bevacizumab (Avastin®): bevacizumab (10mg/kg) intravenously (i.v.) every 2 weeks for a total of 6 doses.
Overall Participants	7
Age, Customized (participants) [Number]
<10 yrs	3 42.9%
>10 and <26 yrs	4 57.1%
Sex: Female, Male (Count of Participants)
Female	2 28.6%
Male	5 71.4%
Race and Ethnicity Not Collected (Count of Participants)

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Received at Least 5 of the 6 Scheduled Doses of Bevacizumab
Description	This pilot study was designed to evaluate the feasibility of treating pediatric patients with CNS radiation necrosis with bevacizumab. Patients enrolled on study were assessed for number of doses of bevacizumab that they received while on study. Participants who successfully received at least 5 of the 6 planned doses of bevacizumab (IV every 2 weeks) without significant events were determined to have met the outcome measure.
Time Frame	13 weeks

Outcome Measure Data

Analysis Population Description

All patients who were enrolled/received a dose of bevacizumab were assessed.

Arm/Group Title	Bevacizumab (Avastin®)
Arm/Group Description	Once enrolled, patients were treated with bevacizumab (10mg/kg) intravenously (i.v.) every 2 weeks for a total of 6 doses. Bevacizumab (Avastin®): bevacizumab (10mg/kg) intravenously (i.v.) every 2 weeks for a total of 6 doses.
Measure Participants	7
Number [participants]	3 42.9%

2. Secondary Outcome

Title	Neurologic Status With Bevacizumab Treatment
Description	Outcome 1: Monitor overall neurologic status and symptoms before, during and 1 month following treatment with bevacizumab.
Time Frame	13 weeks

Outcome Measure Data

Analysis Population Description

Monitor overall neurologic status and symptoms before, during and 1 month following treatment with bevacizumab.

Arm/Group Title	Bevacizumab (Avastin®)
Arm/Group Description	Once enrolled, patients were treated with bevacizumab (10mg/kg) intravenously (i.v.) every 2 weeks for a total of 6 doses. Bevacizumab (Avastin®): bevacizumab (10mg/kg) intravenously (i.v.) every 2 weeks for a total of 6 doses.
Measure Participants	7
Neurologic improvement	4 57.1%
No Neurologic improvement	3 42.9%

3. Secondary Outcome

Title	Corticosteroid Usage With Bevacixumab Treatment
Description	Outcome 2: Dose and duration of corticosteroid use prior to, during, and up to 1 month following bevacizumab treatment will also be collected and evaluated.
Time Frame	13 weeks

Outcome Measure Data

Analysis Population Description

The dose and duration of corticosteroid use was collected and evaluated.

Arm/Group Title	Bevacizumab (Avastin®)
Arm/Group Description	Once enrolled, patients were treated with bevacizumab (10mg/kg) intravenously (i.v.) every 2 weeks for a total of 6 doses. Bevacizumab (Avastin®): bevacizumab (10mg/kg) intravenously (i.v.) every 2 weeks for a total of 6 doses.
Measure Participants	7
Baseline Dexamethasone Dose (mg)	6.0 (4.0)
End of therapy Dexamethasone dose (mg)	2.3 (5.2)

4. Secondary Outcome

Title	Changes in Quality of Life With Bevacizumab Treatment
Description	Outcome 3: To evaluate changes in quality of life before and after treatment with bevacizumab Modified McMasters Scale was used. Minimum score: 1 Maximum score 35. Higher score indicates worse quality of life.
Time Frame	13 weeks

Outcome Measure Data

Analysis Population Description

The participant's quality of life as determined by the Modified McMaster Scale was evaluated at baseline, during and after treatment with bevacizumab

Arm/Group Title	Bevacizumab (Avastin®)
Arm/Group Description	Once enrolled, patients were treated with bevacizumab (10mg/kg) intravenously (i.v.) every 2 weeks for a total of 6 doses. Bevacizumab (Avastin®): bevacizumab (10mg/kg) intravenously (i.v.) every 2 weeks for a total of 6 doses.
Measure Participants	7
Baseline Modified McMasters Score	14.4 (3.6)
End of therapy Modified McMasters Score	15.3 (4.5)

5. Secondary Outcome

Title	Number of Patients With Changes in Neuro-Imaging With Bevacizumab Treatment
Description	Outcome 4: To investigate the neuro-imaging changes in radiation necrosis associated edema, including Mass Resonance (MR) spectroscopy; MRIs (including FLAIR sequences and contrast enhanced images) were evaluated for changes in the radiation necrosis imaging characteristics by a pediatric radiologist. Decreases in gadolinium enhancement, FLAIR signal were considered changes consistent with decreased edema. Tumor size was also evaluated, with a decrease in tumor size indicating decreased edema/improved radiation necrosis
Time Frame	13 weeks

Outcome Measure Data

Analysis Population Description

Descriptive report of radiographic changes with bevacizumab treatment

Arm/Group Title	Bevacizumab (Avastin®)
Arm/Group Description	Once enrolled, patients were treated with bevacizumab (10mg/kg) intravenously (i.v.) every 2 weeks for a total of 6 doses. Bevacizumab (Avastin®): bevacizumab (10mg/kg) intravenously (i.v.) every 2 weeks for a total of 6 doses.
Measure Participants	7
Decreased gadolinium enhancement	7 100%
Decreased FLAIR signal	5 71.4%
Decreased tumor size	5 71.4%

Adverse Events

Time Frame	16 weeks (duration of trial and 30 days post last dose of bevacizumab)
Adverse Event Reporting Description	Adverse events that were possibly, probably or definitely related to study therapy were reported.
Arm/Group Title	Bevacizumab (Avastin®)
Arm/Group Description	Once enrolled, patients were treated with bevacizumab (10mg/kg) intravenously (i.v.) every 2 weeks for a total of 6 doses. Bevacizumab (Avastin®): bevacizumab (10mg/kg) intravenously (i.v.) every 2 weeks for a total of 6 doses.
All Cause Mortality
	Bevacizumab (Avastin®)
	Affected / at Risk (%)	# Events
Total	0/7 (0%)
Serious Adverse Events
	Bevacizumab (Avastin®)
	Affected / at Risk (%)	# Events
Total	0/7 (0%)
Other (Not Including Serious) Adverse Events
	Bevacizumab (Avastin®)
	Affected / at Risk (%)	# Events
Total	4/7 (57.1%)
Gastrointestinal disorders
mucositis	1/7 (14.3%)
Investigations
Aspartate aminotransferase increased	1/7 (14.3%)
lymphocyte count decreased	2/7 (28.6%)
hypophosphatemia	1/7 (14.3%)
hypomagnesemia	1/7 (14.3%)
Musculoskeletal and connective tissue disorders
back pain	1/7 (14.3%)
Renal and urinary disorders
proteinuria	2/7 (28.6%)
renal and urinary disorders, other	1/7 (14.3%)
Respiratory, thoracic and mediastinal disorders
epistaxis	1/7 (14.3%)

Limitations/Caveats

[Not Specified]

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.