Clinical trial NCT02372409: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Glioma
Pilocytic Astrocytoma
Anaplastic Astrocytoma
Glioblastoma
Mixed Oligoastrocytoma
Mixed Glioma
Oligodendroglioma
Optic Glioma
Astrocytoma
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
First posted: 2015-02-26
Enrollment: 6
Sex: ALL
Minimum age (years): 3
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Arm A Only: Number of Participants With Progression-free Survival (PFS)
timeFrame: Up to 5 years from date of registration (median length of follow-up, full range 196 days-1801 days)
measure: Arm A Only: Overall Survival (OS) as Measured by Number of Participants Alive at 5 Years
timeFrame: Up to 5 years from date of registration (median length of follow-up, full range 196 days-1801 days)
measure: Arm B Only: Number of Participants With Progression-free Survival (PFS)
timeFrame: At 6 months
Secondary outcomes:
measure: Change in Quality of Life as Measured by Karnofsky or Lansky Performance Status
timeFrame: At 1 year post-MLA
measure: Serum Biomarkers of Peritumoral Blood Brain Barrier (BBB) Disruption as Measured by Change in Neuron-specific Enolase (NSE)
timeFrame: 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)
measure: Serum Biomarkers of Peritumoral Blood Brain Barrier (BBB) Disruption as Measured by Change in S100B
timeFrame: 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)
measure: Serum Biomarkers of Peritumoral Blood Brain Barrier (BBB) Disruption as Measured by Change in GFAP
timeFrame: 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)
measure: Correlation of MR Imaging With Peritumoral BBB Disruption
timeFrame: 1 year from MLA
measure: Predictive Value of the Peritumoral Permeability Score for Patient Outcome as Measured by PFS
timeFrame: 6 months
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Andrew Cluster, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.