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

NCT02819479 | Completed Phase 2 Results DMC

• 1 other identifier: 14-N0229
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 2

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.

Conditions

Radiation Necrosis

Keywords

Radiation necrosis; Radiation adverse event; Intra-arterial chemotherapy; Bevacizumab; Blood brain barrier disruption; Blood brain barrier breakdown; Arteriovenous malformation; Stereotactic radiosurgery

Outcome Measures

Primary Outcomes (1)

• Change in Radiation Necrosis and Cerebral Edema After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab)

  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.

  Baseline (before treatment), and 3 months and 12 months after single dose intra-arterial Avastin (bevacizumab)

Secondary Outcomes (7)

• Change in Headache Associated Morbidity Measured With MIDAS TOTAL SCORE After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Will be Measured.

  Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab)

• Change in Headache Associated Morbidity Measured With MIDAS DAYS of HEADACHE After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Will be Measured.

  Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab)

• Change in Headache Associated Morbidity Measured With MIDAS PAIN LEVEL After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Will be Measured.

  Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab)

• Change in Headache Measured With Headache Impact Test (HIT-6) After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab)

  Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab)

• Change in Functional Status After a Single Treatment of Low Dose Intra-arterial Bevacizumab

  Baseline (before treatment), Day 1, and at 3 months, and 12 months after single dose intra-arterial Avastin (bevacizumab)

Study Arms (1)

Low-dose Intra-arterial Bevacizumab

EXPERIMENTAL

A single intra-arterial targeted 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; Drug: Low-dose Intra-arterial Bevacizumab

Interventions

25% Mannitol DRUG

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.

Low-dose Intra-arterial Bevacizumab

Low-dose Intra-arterial Bevacizumab DRUG

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

Also known as: Avastin

Low-dose Intra-arterial Bevacizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 either severe headache, seizures, or 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.
• 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 \> or = 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Norton Healthcare: lead
• University of Kentucky: collaborator

Study Sites (2)

University of Kentucky Medical Center

Lexington, Kentucky, 40536, United States

Location

Norton Brownsboro Hospital

Louisville, Kentucky, 40242, United States

Location

Related Publications (1)

• Dashti SR, Kadner RJ, Folley BS, Sheehan JP, Han DY, Kryscio RJ, Carter MB, Shields LBE, Plato BM, La Rocca RV, Spalding AC, Yao TL, Fraser JF. Single low-dose targeted bevacizumab infusion in adult patients with steroid-refractory radiation necrosis of the brain: a phase II open-label prospective clinical trial. J Neurosurg. 2022 Apr 15;137(6):1676-1686. doi: 10.3171/2022.2.JNS212006. Print 2022 Dec 1.

  PMID: 35426830 RESULT

MeSH Terms

Conditions

Arteriovenous Malformations

Interventions

Mannitol; Bevacizumab

Condition Hierarchy (Ancestors)

Vascular Malformations; Cardiovascular Abnormalities; Cardiovascular Diseases; Vascular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Sugar Alcohols; Alcohols; Organic Chemicals; Carbohydrates; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

Pilot Phase 2 Single Arm Clinical Trial with small number of patients. Not powered sufficiently to provide definitive proof for change in current standard of care of medically refractory radiation necrosis of the brain.

Results Point of Contact

• Title: Shervin R. Dashti, MD, PhD, Principal Investigator
• Organization: Norton Neuroscience Institute

shervin.dashti@nortonhealthcare.org

502-394-6390

Study Officials

• Shervin R Dashti, MD,PhD

  Norton Healthcare

  PRINCIPAL INVESTIGATOR

• Justin Fraser, MD

  University of Kentucky

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 9, 2016
• First Posted: June 30, 2016
• Study Start: November 23, 2016
• Primary Completion: June 6, 2019
• Study Completion: June 6, 2019
• Last Updated: May 24, 2022
• Results First Posted: June 28, 2021

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)