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

NCT02372409 | Terminated Phase 2 Results DMC FDA Drug FDA Device

• 1 other identifier: 201502062
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief 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 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.

Conditions

Glioma; Pilocytic Astrocytoma; Anaplastic Astrocytoma; Glioblastoma; Mixed Oligoastrocytoma; Mixed Glioma; Oligodendroglioma; Optic Glioma; Astrocytoma

Outcome Measures

Primary Outcomes (3)

• 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.

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

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

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

• 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.

  At 6 months

Secondary Outcomes (6)

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

  At 1 year post-MLA

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

  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)

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

  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)

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

  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)

• Correlation of MR Imaging With Peritumoral BBB Disruption

  1 year from MLA

Study Arms (2)

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

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

Device: MRI-guided laser ablation; Drug: Doxorubicin; Drug: Etoposide; Device: Dynamic contrast-enhanced (DCE) MRI; Device: Dynamic susceptibility contrast (DSC) MRI

Interventions

MRI-guided laser ablation DEVICE

Also known as: MLA

Arm A (MRI-guided laser ablation); Arm B (MRI-guided laser ablation, doxorubicin, etoposide)

Doxorubicin DRUG

Also known as: Adriamycin

Arm B (MRI-guided laser ablation, doxorubicin, etoposide)

Etoposide DRUG

Also known as: Etoposide phosphate, VP-16, Toposar, Etopophos, VePesid

Arm B (MRI-guided laser ablation, doxorubicin, etoposide)

Dynamic contrast-enhanced (DCE) MRI DEVICE

Also known as: DCE-MRI

Arm A (MRI-guided laser ablation); Arm B (MRI-guided laser ablation, doxorubicin, etoposide)

Dynamic susceptibility contrast (DSC) MRI DEVICE

Also known as: DSC-MRI

Arm A (MRI-guided laser ablation); Arm B (MRI-guided laser ablation, doxorubicin, etoposide)

Eligibility Criteria

• Age: 3 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• 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)

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (12)

• 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.

  PMID: 10602854 BACKGROUND

• 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.

  PMID: 21082374 BACKGROUND

• 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.

  PMID: 21869722 BACKGROUND

• 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.

  PMID: 21720013 BACKGROUND

• 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.

  PMID: 24535317 BACKGROUND

• 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.

  PMID: 8656261 BACKGROUND

• 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.

  PMID: 9470839 BACKGROUND

• 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.

  PMID: 8699237 BACKGROUND

• 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.

  PMID: 17032878 BACKGROUND

• 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.

  PMID: 19257803 BACKGROUND

• 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.

  PMID: 17691714 BACKGROUND

• 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.

  PMID: 22353795 BACKGROUND

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Glioma; Astrocytoma; Glioblastoma; Oligodendroglioma; Optic Nerve Glioma

Interventions

Doxorubicin; Etoposide; etoposide phosphate; Dynamic Contrast Enhanced Magnetic Resonance Imaging; Perfusion Magnetic Resonance Imaging

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Optic Nerve Neoplasms; Cranial Nerve Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Peripheral Nervous System Neoplasms; Cranial Nerve Diseases; Nervous System Diseases; Optic Nerve Diseases; Eye Diseases

Intervention Hierarchy (Ancestors)

Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Magnetic Resonance Imaging; Tomography; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis

Limitations and Caveats

The protocol stated that participants were to be followed for 5 years from participant registration or until death, whichever occurred first. The original consent that the participants signed stated that they would only be followed for 12 months after MLA. Once this issue was discovered, participants were contacted to be reconsented to be followed for 5 years; however, not all participants were able to be reconsented and that is why the results are late.

Results Point of Contact

• Title: Andrew Cluster, M.D.
• Organization: Washington University School of Medicine

acluster@wustl.edu

314-454-6018

Study Officials

• Andrew Cluster, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 13, 2015
• First Posted: February 26, 2015
• Study Start: August 14, 2015
• Primary Completion: March 23, 2023
• Study Completion: March 23, 2023
• Last Updated: November 1, 2024
• Results First Posted: August 9, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)