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GliomaPhase 2NCT02372409

Using MRI-Guided Laser Heat Ablation to Induce Disruption of the Peritumoral Blood Brain Barrier to Enhance Delivery and Efficacy of Treatment of Pediatric Brain Tumors

A Phase 2 study testing MRI-guided laser ablation, Doxorubicin and Etoposide in people with Glioma and Pilocytic Astrocytoma, run by Washington University School of Medicine at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

By employing a combination of advanced MRI techniques and correlative serum biomarkers of blood brain barrier (BBB) disruption, the investigators plan to develop a powerful, first of its kind clinical algorithm in pediatrics whereby the investigators can measure and identify the window of maximal BBB disruption post… Read more about this study

Who is it for?
Ages 3 to 21 years
What is being tested?
MRI-guided laser ablation, Doxorubicin and Etoposide
Could I receive a placebo?
No, everyone receives an active treatment
How many people
6 participants
Where
1 siteUnited States
Study dates
14 Aug 2015to 23 Mar 2023
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 3 to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • ARM A
  • Presumed pediatric gliomas (grades I-IV) on MRI that are determined to be candidates for MLA by the treating neurosurgeon
  • Age 3 to ≤ 21
  • Karnofsky/Lansky performance status ≥ 60%
  • ARM B
  • Recurrent pediatric brain tumors determined candidates for MLA as determined by the treating neurosurgeon.
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  • Unequivocal evidence of tumor progression by MRI
  • There must be an interval of at least 12 weeks from the completion of radiotherapy to study registration except if there is unequivocal evidence for tumor recurrence per RANO criteria. When the interval is less than 12 weeks from the completion of radiotherapy, the use of PET scan is allowed to differentiate between evidence of tumor recurrence and pseudoprogression.
  • Recurrent lesions with dimension and contour that are determined by the treating neurosurgeon to be appropriate for MLA.
  • Age 3 to ≤ 21
  • Karnofsky/Lansky performance status ≥ 60%
  • Adequate cardiac function as determined by a shortening fraction ≥ 27% or left ventricular ejection fraction ≥ 50% by echocardiogram within the past 1 year prior to registration.
  • Prior anthracycline therapy does not exceed 200 mg/m^2 total cumulative dose.
  • Adequate bone marrow and hepatic function as defined below (must be within 7 days of MLA):
  • Absolute neutrophil count (ANC) ≥ 1000/mcl (G-CSF is allowed)
  • Platelets ≥ 100 K/cumm
  • Hemoglobin ≥ 9 g/dL (pRBC transfusion +/- ESA are allowed)
  • ALT ≤ 3 x ULN
  • AST ≤ 3 x ULN
  • ALP ≤ 3 x ULN. If ALP is > 3 x ULN, GGT must be checked and be ≤ 3 x ULN.
  • Bilirubin ≤ 2 x ULN
  • At the time of registration, patient must have recovered from the toxic effects of prior therapy to no more than grade 1 toxicity.
  • At the time of registration, patient must be at least 4 weeks from other prior cytotoxic chemotherapy.
  • 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 must inform her treating physician immediately.
  • Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Who cannot join

  • ARM A
  • Currently receiving or scheduled to receive any other therapies intended to treat the newly diagnosed glioma prior to MLA and the first post-MLA blood collection for correlative studies.
  • Multi-focal or metastatic disease.
  • Pregnant and/or breastfeeding. Premenopausal women must have a negative serum or urine pregnancy test within 14 days of study entry.
  • Inability to undergo MRI due to personal or medical reasons.
  • Known history of HIV or autoimmune diseases requiring immunosuppressant drugs.
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  • ARM B
  • Prior treatment with bevacizumab within 12 weeks of study entry.
  • Previous treatment with complete cumulative doses of daunorubicin, idarubicin, and/or other anthracyclines and anthracenediones that is equivalent to a total dose of > 200 mg/m2 doxorubicin.
  • More than 2 prior relapses (not counting the current relapse being treated on this study).
  • Currently receiving any other investigational agents that are intended as treatments of the relapsed tumor.
  • Multi-focal or metastatic disease.
  • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to doxorubicin or other agents used in the study.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, recent heart attack within the previous 12 months or severe heart problems, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant and/or breastfeeding. Premenopausal women must have a negative serum or urine pregnancy test within 14 days of study entry.
  • Inability to undergo MRI due to personal or medical reasons.
  • Known history of HIV or autoimmune diseases requiring immunosuppressant drugs.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Washington University School of Medicine

    St Louis, Missouri, 63110

Other trials in United States

About this study

Official title: A Pilot Study of Using MRI-Guided Laser Heat Ablation to Induce Disruption of the Peritumoral Blood Brain Barrier to Enhance Delivery and Efficacy of Treatment of Pediatric Brain Tumors

By employing a combination of advanced MRI techniques and correlative serum biomarkers of blood brain barrier (BBB) disruption, the investigators plan to develop a powerful, first of its kind clinical algorithm in pediatrics whereby the investigators can measure and identify the window of maximal BBB disruption post MLA to 1) allow for an alternative to surgery in incompletely resected tumors, 2) allow for optimal chemotherapeutic dosing to achieve the greatest benefits and the least systemic side effects and 3) distinguish subsequent tumor progression from long-term MLA treatment effects. Preliminary data in adult imaging studies have shown that the BBB disruption lasts for several weeks following treatment before returning to a low baseline. This pilot therapeutic study will provide preliminary validation in pediatric patients.

Being tested
MRI-guided laser ablation, Doxorubicin, Etoposide, Dynamic contrast-enhanced (DCE) MRI, Dynamic susceptibility contrast (DSC) MRI
Medical subject headings
Glioma, Astrocytoma, Glioblastoma, Oligodendroglioma, Optic Nerve Glioma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MRI-guided laser ablationDevice

    Also called MLA

  • DoxorubicinDrug

    Also called Adriamycin

  • EtoposideDrug

    Also called Etoposide phosphate, VP-16, Toposar, Etopophos

  • Dynamic contrast-enhanced (DCE) MRIDevice

    Also called DCE-MRI

  • Dynamic susceptibility contrast (DSC) MRIDevice

    Also called DSC-MRI

Study groups in NCT02372409
Study groupRoleWhat they receive
Arm A (MRI-guided laser ablation)Experimental* MLA is a minimally invasive laser surgery currently FDA approved for cytoreductive treatment of brain tumors, both primary and metastatic. MLA employs a small incision in the scalp and skull, through which a thin laser probe is inserted and guided by MR imaging to the core of a tumor mass where it delivers hyperthermic ablation from the core to the rim. * Participants will undergo DCE and DSC-MRI imaging at the following time points: * no more than 3 weeks prior to MLA (OPTIONAL) * within approximately 4 days after MLA * 2-4 weeks after MLA * Every 12 weeks (+/- 7 days) for the first year or until disease progression
Receives: Device: MRI-guided laser ablation; Device: Dynamic contrast-enhanced (DCE) MRI; Device: Dynamic susceptibility contrast (DSC) MRI
Arm B (MRI-guided laser ablation, doxorubicin, etoposide)Experimental* MLA is a minimally invasive laser surgery currently FDA approved for cytoreductive treatment of brain tumors, both primary and metastatic. MLA employs a small incision in the scalp and skull, through which a thin laser probe is inserted and guided by MR imaging to the core of a tumor mass where it delivers hyperthermic ablation from the core to the rim. * Within 7 days of MLA (range 2-14 days) doxorubicin will be given intravenously on an outpatient basis weekly for 6 weeks at a dose of 25 mg/m^2 over 5-30 minutes * Following the completion of doxorubin, etoposide 50 mg/m^2/day will be given orally for 21 days of each 28-day cycle (treatment can continue up to 24 cycles) * Participants will undergo DCE and DSC-MRI imaging at the following time points: * no more than 3 weeks prior to MLA (OPTIONAL) * within approximately 4 days after MLA * 2-4 weeks after MLA * every 8 weeks (+/- 7 days) until 2 years have elapsed or disease progression, whichever comes first
Receives: Device: MRI-guided laser ablation; Drug: Doxorubicin; Drug: Etoposide; Device: Dynamic contrast-enhanced (DCE) MRI; Device: Dynamic susceptibility contrast (DSC) MRI

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Arm A Only: Number of Participants With Progression-free Survival (PFS)

    PFS is followed from start of treatment to time of progression or death, whichever occurs first.

    Measured: Up to 5 years from date of registration (median length of follow-up, full range 196 days-1801 days)

  2. Arm A Only: Overall Survival (OS) as Measured by Number of Participants Alive at 5 Years

    Measured: Up to 5 years from date of registration (median length of follow-up, full range 196 days-1801 days)

  3. Arm B Only: Number of Participants With Progression-free Survival (PFS)

    PFS is followed from start of treatment to time of progression or death, whichever occurs first.

    Measured: At 6 months

Secondary outcomes (6)

  1. Change in Quality of Life as Measured by Karnofsky or Lansky Performance Status

    Score ranges from 100% to 10%. A higher score indicates that the patient has a more normal quality of life.

    Measured: At 1 year post-MLA

  2. Serum Biomarkers of Peritumoral Blood Brain Barrier (BBB) Disruption as Measured by Change in Neuron-specific Enolase (NSE)

    • Arm A patients had blood drawn at the following time points: baseline, 3 days post-MLA, 2-4 weeks post-MLA, and every 12 weeks thereafter for 12 months post-MLA
    • Arm B patients had blood drawn at the following time points: baseline, 3 days post-MLA, week 1, week 2, week 3, week 4, week 5, week 6, and every 8 weeks for the first 2 years or until disease progression, whichever occurs first.
    • Neuron specific enolase is an enzyme involved in glycolysis, which is localized in neurons and axonal processes. Potentially, it escapes into the blood and CSF at the time of neural injury. Elevated serum NSE seemed to correlates with disruption in BBB following MLA and transient increase in BBB permeability.

    Measured: Up to 48 weeks post MRI-guided laser heat ablation (Arm A) or up to 2 years post MRI-guided laser heat ablation (Arm B)

  3. Serum Biomarkers of Peritumoral Blood Brain Barrier (BBB) Disruption as Measured by Change in S100B

    • Arm A patients had blood drawn at the following time points: baseline, 3 days post-MLA, 2-4 weeks post-MLA, and every 12 weeks thereafter for 12 months post-MLA
    • Arm B patients had blood drawn at the following time points: baseline, 3 days post-MLA, week 1, week 2, week 3, week 4, week 5, week 6, and every 8 weeks for the first 2 years or until disease progression, whichever occurs first.
    • S100b is a low-molecular-weight Calcium-binding protein primarily found in astrocytic glial cells of the CNS. It is secreted by astrocytes for neuroprotective and -trophic cellular functions in the CNS. Elevated serum values can be associated with temporal changes in BBB integrity following MLA.

    Measured: Up to 48 weeks post MRI-guided laser heat ablation (Arm A) or up to 2 years post MRI-guided laser heat ablation (Arm B)

  4. Serum Biomarkers of Peritumoral Blood Brain Barrier (BBB) Disruption as Measured by Change in GFAP

    • Arm A patients had blood drawn at the following time points: baseline, 3 days post-MLA, 2-4 weeks post-MLA, and every 12 weeks thereafter for 12 months post-MLA
    • Arm B patients had blood drawn at the following time points: baseline, 3 days post-MLA, week 1, week 2, week 3, week 4, week 5, week 6, and every 8 weeks for the first 2 years or until disease progression, whichever occurs first.
    • The glial fibrillary acidic protein (GFAP) is a classic intermediate filament protein specific to astrocytes in the CNS. GFAP is characteristic of astrocyte- and neural stem cell-derived gliomas in CNS tumors and is used to identify malignancies of glial origin, such as astrocytomas and GBM. Serum GFAP values can be increased with temporal disruption of BBB post-MLA.

    Measured: Up to 48 weeks post MRI-guided laser heat ablation (Arm A) or up to 2 years post MRI-guided laser heat ablation (Arm B)

  5. Correlation of MR Imaging With Peritumoral BBB Disruption

    The linear regression model will used to investigate the correlation between MR imaging and peritumoral BBB disruption. To account for correlation among the repeated measures from the same patient, the longitudinal data will be analyzed with the use of linear generalized estimating equation (GEE). Whether the average measurements differ at the multiple time points will be evaluated through GEE model. Least-square means at each time points will be presented and standard errors will be calculated within the use of the GEE sandwich method when accounting for within-patient correlation.

    Measured: 1 year from MLA

  6. Predictive Value of the Peritumoral Permeability Score for Patient Outcome as Measured by PFS

    Biomarkers with higher correlation coefficient (r approaching 1) will be given higher priority. A minimum r=0.5 is required for inclusion for further analysis and will be used as a peritumoral permeability score. This score will then be correlated with the patient outcome data (as measured by 6 month PFS rate) to determine whether it has a predictive value.

    Measured: 6 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Feb 2015 (estimated)
  2. Study start14 Aug 2015
  3. Primary completion23 Mar 2023
  4. Study completion23 Mar 2023

Why it stopped: Low accruals and competing clinical trials

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
6 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02372409
Sponsor's protocol ID
201502062
Status last verified
Oct 2024
First submitted
13 Feb 2015
Last updated
1 Nov 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
Yes
Individual data sharing
No

Publications

  • Holodny AI, Nusbaum AO, Festa S, Pronin IN, Lee HJ, Kalnin AJ. Correlation between the degree of contrast enhancement and the volume of peritumoral edema in meningiomas and malignant gliomas. Neuroradiology. 1999 Nov;41(11):820-5. doi: 10.1007/s002340050848.

    PubMed 10602854

  • Kassner A, Thornhill R. Measuring the integrity of the human blood-brain barrier using magnetic resonance imaging. Methods Mol Biol. 2011;686:229-45. doi: 10.1007/978-1-60761-938-3_10.

    PubMed 21082374

  • Hawasli AH, Ray WZ, Murphy RK, Dacey RG Jr, Leuthardt EC. Magnetic resonance imaging-guided focused laser interstitial thermal therapy for subinsular metastatic adenocarcinoma: technical case report. Neurosurgery. 2012 Jun;70(2 Suppl Operative):332-7; discussion 338. doi: 10.1227/NEU.0b013e318232fc90.

    PubMed 21869722

  • Gong W, Wang Z, Liu N, Lin W, Wang X, Xu D, Liu H, Zeng C, Xie X, Mei X, Lu W. Improving efficiency of adriamycin crossing blood brain barrier by combination of thermosensitive liposomes and hyperthermia. Biol Pharm Bull. 2011;34(7):1058-64. doi: 10.1248/bpb.34.1058.

    PubMed 21720013

  • Quick J, Gessler F, Dutzmann S, Hattingen E, Harter PN, Weise LM, Franz K, Seifert V, Senft C. Benefit of tumor resection for recurrent glioblastoma. J Neurooncol. 2014 Apr;117(2):365-72. doi: 10.1007/s11060-014-1397-2. Epub 2014 Feb 15.

    PubMed 24535317

  • Ashley DM, Meier L, Kerby T, Zalduondo FM, Friedman HS, Gajjar A, Kun L, Duffner PK, Smith S, Longee D. Response of recurrent medulloblastoma to low-dose oral etoposide. J Clin Oncol. 1996 Jun;14(6):1922-7. doi: 10.1200/JCO.1996.14.6.1922.

    PubMed 8656261

  • Davidson A, Gowing R, Lowis S, Newell D, Lewis I, Dicks-Mireaux C, Pinkerton CR. Phase II study of 21 day schedule oral etoposide in children. New Agents Group of the United Kingdom Children's Cancer Study Group (UKCCSG). Eur J Cancer. 1997 Oct;33(11):1816-22. doi: 10.1016/s0959-8049(97)00201-3.

    PubMed 9470839

  • Fulton D, Urtasun R, Forsyth P. Phase II study of prolonged oral therapy with etoposide (VP16) for patients with recurrent malignant glioma. J Neurooncol. 1996 Feb;27(2):149-55. doi: 10.1007/BF00177478.

    PubMed 8699237

  • Law M, Young R, Babb J, Rad M, Sasaki T, Zagzag D, Johnson G. Comparing perfusion metrics obtained from a single compartment versus pharmacokinetic modeling methods using dynamic susceptibility contrast-enhanced perfusion MR imaging with glioma grade. AJNR Am J Neuroradiol. 2006 Oct;27(9):1975-82.

    PubMed 17032878

  • Blyth BJ, Farhavar A, Gee C, Hawthorn B, He H, Nayak A, Stocklein V, Bazarian JJ. Validation of serum markers for blood-brain barrier disruption in traumatic brain injury. J Neurotrauma. 2009 Sep;26(9):1497-1507. doi: 10.1089/neu.2008.0738.

    PubMed 19257803

  • Dunn GP, Dunn IF, Curry WT. Focus on TILs: Prognostic significance of tumor infiltrating lymphocytes in human glioma. Cancer Immun. 2007 Aug 13;7:12.

    PubMed 17691714

  • Dunn GP, Fecci PE, Curry WT. Cancer immunoediting in malignant glioma. Neurosurgery. 2012 Aug;71(2):201-22; discussion 222-3. doi: 10.1227/NEU.0b013e31824f840d.

    PubMed 22353795

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing MRI-guided laser ablation, Doxorubicin and Etoposide in people with Glioma and Pilocytic Astrocytoma, run by Washington University School of Medicine at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 25 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 1 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 9 Aug 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Arm A Only: Number of Participants With Progression-free Survival (PFS) (time frame: Up to 5 years from date of registration (median length of follow-up, full range 196 days-1801 days)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02372409, which also lists 12 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Nov 2024.

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