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Low-dose Intra-arterial Bevacizumab for Edema and Radiation Necrosis Therapeutic Intervention (LIBERTI) (LIBERTI)

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ClinicalTrials.gov Identifier: NCT02819479
Recruitment Status : Active, not recruiting
First Posted : June 30, 2016
Last Update Posted : October 11, 2017
Sponsor:
Collaborator:
Information provided by (Responsible Party):

Study Description
Brief Summary:
To assess the overall safety and efficacy of intra-arterial (IA) bevacizumab for the treatment of radiation necrosis. A single 2.5 mg/kg dose of bevacizumab will be given intra-arterially after osmotic blood-brain-barrier disruption.

Condition or disease Intervention/treatment Phase
Radiation Necrosis Drug: 25% Mannitol Drug: Low-dose Intra-arterial Bevacizumab Phase 2

  Show Detailed Description

Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Low-dose Intra-arterial Bevacizumab for Edema and Radiation Necrosis Therapeutic Intervention (LIBERTI)
Study Start Date : November 2016
Estimated Primary Completion Date : November 2018
Estimated Study Completion Date : November 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Edema
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: Low-dose Intra-arterial Bevacizumab
A single intra-arterial dose of 2.5 mg/kg bevacizumab will be administered after osmotic blood-brain-barrier disruption with intra-arterial 25% mannitol at rate of 4-12 ml/sec for 30 seconds.
Drug: 25% Mannitol

Route of administration:

In this study, the first step of the treatment will be performing osmotic blood-brain-barrier disruption with administration of intra-arterial 25% Mannitol into the appropriate cervical artery.

Drug: Low-dose Intra-arterial Bevacizumab

Route of administration:

In this study, the second step of the treatment will be administering intra-arterial bevacizumab into the appropriate cervical artery.

Other Name: Avastin


Outcome Measures

Primary Outcome Measures :
  1. Decrease in radiation necrosis and cerebral edema after a single treatment of low dose intra-arterial bevacizumab [ Time Frame: Day 0, and at 3 months, and 12 months ]
    Imaging response to therapy will be quantitatively assessed on MRI using volumetric analysis. Regions of T2 and FLAIR prolongation above contralateral white matter will be calculated and quantified in cubic centimeters. Region of interest (ROI) will be created using a semi-automated, thresholding and region-growing technique. Enhancement of the lesion will be calculated using similar volumetric ROI analysis with a contrast threshold of 40% above background and measured in cubic centimeters.


Secondary Outcome Measures :
  1. Decrease in steroid usage after a single treatment of low dose intra-arterial bevacizumab [ Time Frame: Day 0, and at 3 months, and 12 months ]
    To assess the utility of intra-arterial bevacizumab treatment in allowing decreased steroid usage, the quantity of steroid use (measured as mg of decadron per day) will be documented.

  2. Quantitative improvement in headache after a single treatment of low dose intra-arterial bevacizumab [ Time Frame: Day 0, and at 6 weeks, 3 months, 6 months, and 12 months ]
    Quantitative improvement in headache will be assessed by performing the Headache Impact Test (HIT-6), which is a fixed-length 6-item questionnaire. The score for this questionnaire can range from 36 to 78, with higher scores indicating worse headache burden.

  3. Improvement in headache associated morbidity after a single treatment of low dose intra-arterial bevacizumab will be measured. [ Time Frame: Day 0, and at 6 weeks, 3 months, 6 months, and 12 months ]
    We will determine how severely headache affect the patient's life before and after treatment by performing the MIDAS 5-item questionnaire: Score of 0 to 5 signifies little or no disability, score of 6 to 10, signifies mild disability, score of 11 to 20 signifies moderate disability, and score of 21+ signifies severe disability.

  4. Post-operative neurocognitive sequelae of intra-arterial bevacizumab [ Time Frame: Day 0, and at 3 months, and 12 months ]
    In order to investigate the immediate and post-operative neurocognitive sequelae of intra-arterial bevacizumab, patients who consent to a formal neuropsychological battery will be tested. Subtests from the NAB (Neuropsychological Assessment Battery, Stern & White, PAR Inc.) have been chosen for brevity, sensitivity, and due to the wide range of available normative data (ages 18-97). In addition, the Wechsler Test of Adult Reading (WTAR, Pearson Inc.) will be administered to provide an estimate of premorbid cognitive functioning.

  5. Adverse events after a single treatment of low dose intra-arterial bevacizumab [ Time Frame: Day 0, and at 3 months, and 12 months ]
    Safety of intra-arterial bevacizumab will be assessed by noting the number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  6. Neurological improvement after a single treatment of low dose intra-arterial bevacizumab [ Time Frame: Day 0, and at 3 months, and 12 months ]
    Objective improvement in neurological exam will be assessed by performing serial neurological exams.

  7. Improvement in functional status after a single treatment of low dose intra-arterial bevacizumab [ Time Frame: Day 0, and at 3 months, and 12 months ]
    Quantitative improvement in functional status will be assessed by performing Karnofsky Performance Status Scale (KPS). The KPS score can range from 0 to 100.

  8. Improvement in quality of life after a single treatment of low dose intra-arterial bevacizumab [ Time Frame: Day 0, and at 6 weeks, 3 months, 6 months, and 12 months ]
    Quantitative improvement in quality of life will be assessed by performing CDC HRQOL-14 "Healthy Days Measure." This survey contains 14 items to measure health-related quality of life. It consists of three modules: the 4-item Healthy Days Core Module (CDC HDQOL-4), 5-item Activity Limitations Module, and 5-item Healthy Days Symptom Module. The items in this survey are either subjective and require yes/no answer, or they involve the number of days during the past 30 days that the patient had problems secondary to different physical or mental health issues.


Other Outcome Measures:
  1. Cost analysis of a single treatment of low dose intra-arterial bevacizumab compared to conventional IV-bevacizumab regiment [ Time Frame: At 12 months ]
    Cost analysis of a single treatment of low dose intra-arterial bevacizumab after osmotic blood-brain-barrier disruption as compared to conventional intravenous bevacizumab use for radiation necrosis (7.5 mg/kg IV-Bevacizumab every 3 weeks for 4 cycles)


Eligibility Criteria

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patients must have radiation necrosis based on radiographic evidence defined as:

  • Increased T1 contrast enhancement in the radiated area with central hypointensity
  • Increased surrounding vasogenic edema on FLAIR MRI images
  • The underlying lesion prompting the radiation can include: Benign lesions such as AVM, Meningioma, schwannoma, trigeminal neuralgia: No biopsy is necessary
  • Radiation necrosis must be symptomatic, including severe headache, seizures, and neurological deficits.
  • Radiation necrosis must be refractory to steroid treatment; defined as failing a 3-week steroid regiment or not tolerating steroids because of side effects. Beyond 3 weeks, the side effects of steroid therapy worsen rapidly. The patient may receive other therapies such as Vitamine E, Pentoxyfylline, and hyperbaric oxygen during the trial.

Other inclusion criteria include:

  • Age >18 years.
  • Ability to understand and the willingness to sign a written informed consent document.
  • Both men and women and members of all races and ethnic groups are eligible for this trial.
  • Karnofsky Performance Status >70%.
  • Life expectancy of greater than 3 months.
  • Patients must have normal organ and marrow function as defined below:

leukocytes greater than equal to1,500/mcL platelets greater than equal to 85,000/mcL creatinine less than equal to 1.8 mg/dl

•Birth Control: The effects of Bevacizumab on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Women of childbearing age will have a urine pregnancy test immediately before each IA Bevacizumab treatment.

Exclusion Criteria:

  • Patients may not be started on any other investigational agents during the course of this trial. They may however continue previous medical regiments aimed for treatment of radiation necrosis. These include steroids, vitamin E, pentoxiphylline, and hyperbaric oxygen. We feel that these treatments are generally ineffectual and would not confound the results.
  • Malignant brain tumor
  • Concomitant use of anticoagulation agents including Coumadin, anticoagulation dose Lovenox or Arixtra. Aspirin is acceptable.
  • Active bleeding or pathological condition that carries high risk of bleeding.
  • Abdominal fistula, abscess, or gastrointestinal tract perforation 28 days of study entry.
  • Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Any major surgery in the prior 4 weeks. Also any major surgery expected to be performed in the ensuing 4 weeks after treatment.
  • Pregnant women are excluded from this study because Bevacizumab is expected to disrupt angiogenesis during pregnancy with the potential for teratogenic or abortive effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Bevacizumab, breastfeeding should be discontinued if the mother is treated with Bevacizumab.
  • HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with Bevacizumab.
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02819479


Locations
United States, Kentucky
University of Kentucky Medical Center
Lexington, Kentucky, United States, 40536
Norton Brownsboro Hospital
Louisville, Kentucky, United States, 40242
Sponsors and Collaborators
Norton Healthcare
University of Kentucky
Investigators
Principal Investigator: Shervin R Dashti, MD,PhD Norton Healthcare
Principal Investigator: Justin Fraser, MD University of Kentucky
More Information

Responsible Party: Shervin Dashti, MD, Principal Investigator, Norton Healthcare
ClinicalTrials.gov Identifier: NCT02819479     History of Changes
Other Study ID Numbers: 14-N0229
First Posted: June 30, 2016    Key Record Dates
Last Update Posted: October 11, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Shervin Dashti, MD, Norton Healthcare:
Radiation necrosis
Radiation adverse event
Intra-arterial chemotherapy
Bevacizumab
Blood brain barrier disruption
Blood brain barrier breakdown

Additional relevant MeSH terms:
Necrosis
Pathologic Processes
Bevacizumab
Mannitol
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Diuretics, Osmotic
Diuretics
Natriuretic Agents