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

• ClinicalTrials.gov Identifier: NCT02372409
• Recruitment Status: Recruiting
• First Posted: February 26, 2015
• Last Update Posted: May 23, 2019
• Sponsor: Washington University School of Medicine
• Information provided by (Responsible Party): Washington University School of Medicine

Tracking Information

• First Submitted Date: February 13, 2015
• First Posted Date: February 26, 2015
• Last Update Posted Date: May 23, 2019
• Actual Study Start Date: August 14, 2015
• Estimated Primary Completion Date: October 30, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 20, 2015)

• Arm A only: Progression-free survival (PFS) [ Time Frame: Up to 5 years ]
  PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
• Arm A only: Overall survival (OS) [ Time Frame: Up to 5 years ]
• Arm B only: Progression-free survival (PFS) [ Time Frame: 6 months ]
  PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
• Arm B only: Quality of life (QOL) [ Time Frame: 1 year from MLA ]
  -Using Karnofsky or Lansky performance status in patients following MLA and in patients who receive doxorubicin and maintenance etoposide after MLA.

• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT02372409 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: February 20, 2015)

• Correlation of MR imaging with peritumoral BBB disruption [ Time Frame: 1 year from MLA ]
  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.
• Serum biomarkers of peritumoral BBB disruption [ Time Frame: 1 year from MLA ]
  Since the investigators do not know which biomarkers will have better correlation with the Ktrans data from DCE and DSC-MRI and patients' survival outcome, the investigators plan to determine the levels of all 3 biomarkers in a blinded fashion. Once both the Ktrans and biomarker levels are available, the investigators will determine which biomarkers have the closest correlation that is statistically significant with the Ktrans. Pearson correlation coefficient (r) will be determined for each biomarker and Ktrans value. Biomarkers with higher correlation coefficient (r approaching 1) will be given higher priority.
• Predictive value of the peritumoral permeability score for patient outcome as measured by PFS [ Time Frame: 6 months ]
  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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• Device: MRI-guided laser ablation
  Other Name: MLA
• Drug: Doxorubicin
  Other Name: Adriamycin
• Drug: Etoposide
  Other Names:

  • Etoposide phosphate
  • VP-16
  • Toposar
  • Etopophos
  • VePesid
• Device: Dynamic contrast-enhanced (DCE) MRI
  Other Name: DCE-MRI
• Device: Dynamic susceptibility contrast (DSC) MRI
  Other Name: DSC-MRI

Study Arms

• Experimental: Arm A (MRI-guided laser ablation)
  • 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
  Interventions:

  • Device: MRI-guided laser ablation
  • Device: Dynamic contrast-enhanced (DCE) MRI
  • Device: Dynamic susceptibility contrast (DSC) MRI
• Experimental: Arm B (MRI-guided laser ablation, doxorubicin, etoposide)
  • 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
  Interventions:

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

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.
• 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.
• 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.
• Gong W, Wang Z, Liu N, Lin W, Wang X, Xu D, Liu H, Zeng C, Xie X, Mei X, Lü W. Improving efficiency of adriamycin crossing blood brain barrier by combination of thermosensitive liposomes and hyperthermia. Biol Pharm Bull. 2011;34(7):1058-64.
• Quick J, Gessler F, Dützmann 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.
• 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.
• 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.
• 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.
• 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.
• Blyth BJ, Farhavar A, Gee C, Hawthorn B, He H, Nayak A, Stöcklein 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.
• 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. Review.
• 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. Review.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 20, 2015): 12
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 30, 2020
• Estimated Primary Completion Date: October 30, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

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)
  • 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).

Exclusion Criteria:

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.
• Inability to undergo MRI due to personal or medical reasons.
• Known history of HIV or autoimmune diseases requiring immunosuppressant drugs.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 3 Years to 21 Years (Child, Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Karen Gauvain, M.D.; (314) 454-4457; gauvaink@wustl.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02372409
• Other Study ID Numbers: 201502062
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Washington University School of Medicine
• Study Sponsor: Washington University School of Medicine
• Collaborators: Not Provided

Investigators

• Principal Investigator: Karen Gauvain, M.D.; Washington University School of Medicine

• PRS Account: Washington University School of Medicine
• Verification Date: May 2019