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

• MRI-guided laser ablation (Device), also known as MLA
• Doxorubicin (Drug), also known as Adriamycin
• Etoposide (Drug), also known as Etoposide phosphate, VP-16, Toposar, Etopophos, VePesid
• Dynamic contrast-enhanced (DCE) MRI (Device), also known as DCE-MRI
• Dynamic susceptibility contrast (DSC) MRI (Device), also known as DSC-MRI

Primary outcomes

• Arm A Only: Number of Participants With Progression-free Survival (PFS) [Up to 5 years from date of registration (median length of follow-up, full range 196 days-1801 days)]: PFS is followed from start of treatment to time of progression or death, whichever occurs first.
• 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) [At 6 months]: PFS is followed from start of treatment to time of progression or death, whichever occurs first.

Secondary outcomes

• Change in Quality of Life as Measured by Karnofsky or Lansky Performance Status [At 1 year post-MLA]: Score ranges from 100% to 10%. A higher score indicates that the patient has a more normal quality of life.
• 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)]: * 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.
• 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)]: * 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.
• 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)]: * 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.
• Correlation of MR Imaging With Peritumoral BBB Disruption [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.
• Predictive Value of the Peritumoral Permeability Score for Patient Outcome as Measured by PFS [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.

Sex: All, ages: 3 Years to 21 Years

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.

Participant flow

Outcome results

• Arm A Only: Number of Participants With Progression-free Survival (PFS) (Primary), Count of participants, Participants: Arm A (MRI-guided Laser Ablation) 4; Arm B (MRI-guided Laser Ablation, Doxorubicin, Etoposide)
• Arm A Only: Overall Survival (OS) as Measured by Number of Participants Alive at 5 Years (Primary), Count of participants, Participants: Arm A (MRI-guided Laser Ablation) 5; Arm B (MRI-guided Laser Ablation, Doxorubicin, Etoposide)
• Arm B Only: Number of Participants With Progression-free Survival (PFS) (Primary), Count of participants, Participants: Arm A (MRI-guided Laser Ablation) ; Arm B (MRI-guided Laser Ablation, Doxorubicin, Etoposide) 0
• Change in Quality of Life as Measured by Karnofsky or Lansky Performance Status (Secondary), Number, score on a scale: Patient 1: Arm A (MRI-guided Laser Ablation) 90; Patient 2: Arm A (MRI-guided Laser Ablation) 100; Patient 3: Arm A (MRI-guided Laser Ablation) 80; Patient 4: Arm A (MRI-guided Laser Ablation) 100; Patient 5: Arm A (MRI-guided Laser Ablation) 100
• Serum Biomarkers of Peritumoral Blood Brain Barrier (BBB) Disruption as Measured by Change in Neuron-specific Enolase (NSE) (Secondary), Number, ng/ml: Patient 1: Arm A (MRI-guided Laser Ablation) 29.0219; Patient 4: Arm A (MRI-guided Laser Ablation) 58.3406; Patient 3: Arm A (MRI-guided Laser Ablation) 3.1823; Patient 5: Arm A (MRI-guided Laser Ablation) 13.1819; Patient 6: Arm A (MRI-guided Laser Ablation) 7.5534; Patient 1: Arm B (MRI-guided Laser Ablation, Doxorubicin, Etoposide) 11.5114
• Serum Biomarkers of Peritumoral Blood Brain Barrier (BBB) Disruption as Measured by Change in S100B (Secondary), Number, pg/ml: Patient 1: Arm A (MRI-guided Laser Ablation) ; Patient 4: Arm A (MRI-guided Laser Ablation) 79.74; Patient 3: Arm A (MRI-guided Laser Ablation) ; Patient 5: Arm A (MRI-guided Laser Ablation) ; Patient 6: Arm A (MRI-guided Laser Ablation) ; Patient 1: Arm B (MRI-guided Laser Ablation, Doxorubicin, Etoposide)
• Serum Biomarkers of Peritumoral Blood Brain Barrier (BBB) Disruption as Measured by Change in GFAP (Secondary), Number, ng/ml
• Correlation of MR Imaging With Peritumoral BBB Disruption (Secondary)
• Predictive Value of the Peritumoral Permeability Score for Patient Outcome as Measured by PFS (Secondary)

Adverse events

Time frame: -Reportable adverse events will be tracked for 30 days following the last day of study treatment for patients in Arm B and for 30 days following the MLA for patients in Arm A. -All-cause mortality will be collected from start of treatment up to 5 years after start of treatment (median length of follow-up 413.5 days, full range 366 days-1801 days).

Other adverse events by term

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.

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• Study Protocol and Statistical Analysis Plan (PDF, 2020-08-11)

• Andrew Cluster, M.D., Principal investigator, Washington University School of Medicine