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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Glioma, Pilocytic Astrocytoma, Anaplastic Astrocytoma, Glioblastoma, Mixed Oligoastrocytoma, Mixed Glioma, Oligodendroglioma, Optic Glioma, Astrocytoma

Intervention / Treatment
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* Device: MRI-guided laser ablation
* Drug: Doxorubicin
* Drug: Etoposide
* Device: Dynamic contrast-enhanced (DCE) MRI
* Device: Dynamic susceptibility contrast (DSC) MRI


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (MRI-guided laser ablation)<br>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<br> <br> * Other names: MLA;Device: Dynamic contrast-enhanced (DCE) MRI<br> <br> * Other names: DCE-MRI;Device: Dynamic susceptibility contrast (DSC) MRI<br> <br> * Other names: DSC-MRI;|
| Experimental: Arm B (MRI-guided laser ablation, doxorubicin, etoposide)<br>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<br> <br> * Other names: MLA;Drug: Doxorubicin<br> <br> * Other names: Adriamycin;Drug: Etoposide<br> <br> * Other names: VePesid;Device: Dynamic contrast-enhanced (DCE) MRI<br> <br> * Other names: DCE-MRI;Device: Dynamic susceptibility contrast (DSC) MRI<br> <br> * Other names: DSC-MRI;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 1 year from MLA | 
| Serum biomarkers of peritumoral BBB disruption | 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. | 1 year from MLA | 
| 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. | 6 months |