600 POSTER Hematologic pharmacodynamics linked to the pharmacokinetics of berubicin (B), a blood–brain barrier penetrating anthracycline active against high grade glioma, in phase I/II clinical trials

2008 ◽  
Vol 6 (12) ◽  
pp. 187-188 ◽  
Author(s):  
R. Kazerooni ◽  
C. Conrad ◽  
M.J. Johansen ◽  
M. Sakamoto ◽  
I. Fokt ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Blood Brain Barrier ◽  
High Grade Glioma ◽  
Brain Barrier ◽  
High Grade ◽  
Blood Brain

Intraarterial delivery of bevacizumab and cetuximab utilizing blood-brain barrier disruption in children with high-grade glioma and diffuse intrinsic pontine glioma: results of a phase I trial

2021 ◽  
pp. 1-9
Author(s):  
Heather J. McCrea ◽  
Jana Ivanidze ◽  
Ashley O’Connor ◽  
Eliza H. Hersh ◽  
John A. Boockvar ◽  
...  
Keyword(s):  
Phase I ◽  
Blood Brain Barrier ◽  
Stable Disease ◽  
Phase I Trial ◽  
Progressive Disease ◽  
High Grade Glioma ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Brain Barrier ◽  
High Grade ◽  
Pontine Glioma

OBJECTIVE Delivery of drugs intraarterially to brain tumors has been demonstrated in adults. In this study, the authors initiated a phase I trial of superselective intraarterial cerebral infusion (SIACI) of bevacizumab and cetuximab in pediatric patients with refractory high-grade glioma (diffuse intrinsic pontine glioma [DIPG] and glioblastoma) to determine the safety and efficacy in this population. METHODS SIACI was used to deliver mannitol (12.5 ml of 20% mannitol) to disrupt the blood-brain barrier (BBB), followed by bevacizumab (15 mg/kg) and cetuximab (200 mg/m2) to target VEGF and EGFR, respectively. Patients with brainstem tumors had a balloon inflated in the distal basilar artery during mannitol infusion. RESULTS Thirteen patients were treated (10 with DIPG and 3 with high-grade glioma). Toxicities included grade I epistaxis (2 patients) and grade I rash (2 patients). There were no dose-limiting toxicities. Of the 10 symptomatic patients, 6 exhibited subjective improvement; 92% showed decreased enhancement on day 1 posttreatment MRI. Of 10 patients who underwent MRI at 1 month, 5 had progressive disease and 5 had stable disease on FLAIR, whereas contrast-enhanced scans demonstrated progressive disease in 4 patients, stable disease in 2, partial response in 2, and complete response in 1. The mean overall survival for the 10 DIPG patients was 519 days (17.3 months), with a mean posttreatment survival of 214.8 days (7.2 months). CONCLUSIONS SIACI of bevacizumab and cetuximab was well tolerated in all 13 children. The authors’ results demonstrate safety of this method and warrant further study to determine efficacy. As molecular targets are clarified, novel means of bypassing the BBB, such as intraarterial therapy and convection-enhanced delivery, become more critical. Clinical trial registration no.: NCT01884740 (clinicaltrials.gov)

scholarly journals Comparative study of preclinical mouse models of high-grade glioma for nanomedicine research: the importance of reproducing blood-brain barrier heterogeneity

Theranostics ◽  
2020 ◽  
Vol 10 (14) ◽  
pp. 6361-6371 ◽  
Author(s):  
Caterina Brighi ◽  
Lee Reid ◽  
Laura A Genovesi ◽  
Marija Kojic ◽  
Amanda Millar ◽  
...  
Keyword(s):  
Comparative Study ◽  
Blood Brain Barrier ◽  
Mouse Models ◽  
High Grade Glioma ◽  
Brain Barrier ◽  
High Grade ◽  
Blood Brain

scholarly journals THER-15. FUNCTIONALIZED NANOPARTICLE TRAFFICKING ASSESSED IN A NOVEL MICROFLUIDIC MODEL OF THE BLOOD-BRAIN BARRIER WITH HIGH GRADE GLIOMA SPHEROIDS

2019 ◽  
Vol 21 (Supplement_2) ◽  
pp. ii117-ii117
Author(s):  
Joelle P Straehla ◽  
Cynthia Hajal ◽  
Tamara Dacoba ◽  
Roger D Kamm ◽  
Paula T Hammond
Keyword(s):  
Blood Brain Barrier ◽  
High Grade Glioma ◽  
Brain Barrier ◽  
High Grade ◽  
Blood Brain

scholarly journals Marizomib alone or in combination with bevacizumab in patients with recurrent glioblastoma: phase I/II clinical trial data

2021 ◽  
Author(s):  
Daniela A Bota ◽  
Warren Mason ◽  
Santosh Kesari ◽  
Rajiv Magge ◽  
Benjamin Winograd ◽  
...  
Keyword(s):  
Phase I ◽  
Blood Brain Barrier ◽  
Dose Escalation ◽  
Safety Profile ◽  
Clinical Trial Data ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Brain Barrier ◽  
Part C ◽  
Blood Brain

Abstract Background This phase I/II trial in patients with recurrent glioblastoma (GBM) evaluates the safety and preliminary efficacy of marizomib, an irreversible pan-proteasome inhibitor that crosses the blood–brain barrier. Patients and Methods Part A assessed the safety and efficacy of marizomib monotherapy. In Part B, escalating doses of marizomib (0.5–0.8 mg/m2) in combination with bevacizumab were evaluated. Part C explored intra-patient dose escalation of marizomib (0.8–1.0 mg/m2) for the combination. Results In Part A, 30 patients received marizomib monotherapy. The most common AEs were fatigue (66.7%), headache (46.7%), hallucination (43.3%), and insomnia (43.3%). One patient (3.3%) achieved a partial response. In Part B, the recommended phase II dose of marizomib was 0.8 mg/m2 when combined with bevacizumab 10 mg/kg. In Part C, dose escalation to 1.0 mg/m2 was not tolerated. Pooled analysis of 67 patients treated with marizomib ≤0.8 mg/m2 and bevacizumab showed a non-overlapping safety profile consistent with the known safety profile of each agent: the most common grade ≥3 AEs were hypertension (16.4%), confusion (13.4%), headache (10.4%), and fatigue (10.4%). The overall response rate was 34.3%, including 2 patients with complete response. Six-month progression-free survival was 29.8%; median overall survival was 9.1 months. Conclusions The safety profile of marizomib as monotherapy and in combination with bevacizumab was consistent with previous observations that marizomib crosses the blood–brain barrier. Preliminary efficacy did not demonstrate a meaningful benefit of the addition of marizomib to bevacizumab for the treatment of recurrent GBM.

scholarly journals Complementary role of mathematical modeling in preclinical glioblastoma: differentiating poor drug delivery from drug insensitivity

2021 ◽  
Author(s):  
Javier C. Urcuyo ◽  
Susan Christine Massey ◽  
Andrea Hawkins-Daarud ◽  
Bianca-Maria Marin ◽  
Danielle M. Burgenske ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Drug Delivery ◽  
Clinical Trials ◽  
Treatment Response ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Significant Heterogeneity ◽  
Current Standard ◽  
Modeling Approach ◽  
Blood Brain

AbstractGlioblastoma is the most malignant primary brain tumor with significant heterogeneity and a limited number of effective therapeutic options. Many investigational targeted therapies have failed in clinical trials, but it remains unclear if this results from insensitivity to therapy or poor drug delivery across the blood-brain barrier. Using well-established EGFR-amplified patient-derived xenograft (PDX) cell lines, we investigated this question using an EGFR-directed therapy. With only bioluminescence imaging, we used a mathematical model to quantify the heterogeneous treatment response across the three PDX lines (GBM6, GBM12, GBM39). Our model estimated the primary cause of intracranial treatment response for each of the lines, and these findings were validated with parallel experimental efforts. This mathematical modeling approach can be used as a useful complementary tool that can be widely applied to many more PDX lines. This has the potential to further inform experimental efforts and reduce the cost and time necessary to make experimental conclusions.Author summaryGlioblastoma is a deadly brain cancer that is difficult to treat. New therapies often fail to surpass the current standard of care during clinical trials. This can be attributed to both the vast heterogeneity of the disease and the blood-brain barrier, which may or may not be disrupted in various regions of tumors. Thus, while some cancer cells may develop insensitivity in the presence of a drug due to heterogeneity, other tumor areas are simply not exposed to the drug. Being able to understand to what extent each of these is driving clinical trial results in individuals may be key to advancing novel therapies. To address this challenge, we used mathematical modeling to study the differences between three patient-derived tumors in mice. With our unique approach, we identified the reason for treatment failure in each patient tumor. These results were validated through rigorous and time-consuming experiments, but our mathematical modeling approach allows for a cheaper, quicker, and widely applicable way to come to similar conclusions.

A phase I/IIa study to evaluate the safety and efficacy of blood-brain barrier (BBB) opening with the SonoCloud-9 implantable ultrasound device in recurrent glioblastoma patients receiving IV carboplatin.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2049-2049
Author(s):  
Ahmed Idbaih ◽  
Francois Ducray ◽  
Roger Stupp ◽  
Nathalie Baize ◽  
Olivier L. Chinot ◽  
...  
Keyword(s):  
Phase I ◽  
Blood Brain Barrier ◽  
Tissue Concentration ◽  
Primary Objective ◽  
Recurrent Glioblastoma ◽  
Mass Spectrometry Data ◽  
Brain Barrier ◽  
Pulsed Ultrasound ◽  
Blurred Vision ◽  
Blood Brain

2049 Background: Low intensity pulsed ultrasound (LIPU) in conjunction with intravenous microbubbles can transiently and reversibly disrupt the blood-brain barrier (BBB), allowing for an increase in the tissue concentration of chemotherapy agents in the brain. Mass spectrometry data from preclinical models (mouse, swine) showed a > 5x enhancement in carboplatin brain concentrations, which correlated well with the spatial distribution of a Gadolinium (Gd) contrast agent used for magnetic resonance imaging (MRI). Methods: The primary objective of this phase I/IIa study (NCT03744026) was to demonstrate the safety of BBB disruption using LIPU in patients with recurrent glioblastoma. This study was a 3+3 design using escalating numbers (3, 6, 9) of activated 1 MHz ultrasound emitters. Nine patients were treated in the escalation phase and another 12 patients were treated with 9 emitters in the expansion phase. Eligibility included recurrent GBM (any recurrence) with a maximum tumor size of < 70 mm. The SonoCloud-9 device (CarThera, Paris, France) was implanted during tumor debulking/resection surgery and replaced the bone flap, with the device targeting the tumor and surrounding peritumoral brain. The device was activated every four weeks for a duration of 270 seconds, concomitantly with IV DEFINITY microbubbles (10 ml/kg), to disrupt the BBB prior to administration of carboplatin (AUC 4-6). MRI was performed to verify safety and evaluate efficacy of BBB disruption with Gd enhancement. Results: No DLTs were observed. The overall tolerance of the SonoCloud-9 implant was good, with two transient, manageable grade 3 wound infections and one grade 1 acquired meningocele event considered as probably related to the overall procedure. The most frequent neurologic adverse events were grade 1 blurred vision (5%) and dizziness (5%). Conclusions: Significant Gd enhancement was observed after more than 90% of sonication sessions, suggesting effective BBB disruption and carboplatin enhancement. Clinical trial information: NCT03744026.

Differences in the distribution of methotrexate into high grade gliomas following intravenous administration, as monitored by microdialysis, are associated with blood brain barrier integrity

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1548-1548 ◽  
Author(s):  
J. J. Olson ◽  
J. O. Blakeley ◽  
S. A. Grossman ◽  
J. Weingart ◽  
A. Rashid ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Half Life ◽  
Extracellular Fluid ◽  
Brain Barrier ◽  
Published Data ◽  
High Grade ◽  
Blood Brain ◽  
Drug Concentrations ◽  
High Grade Gliomas

1548 Background: Microdialysis (MD) is an accepted technique to monitor neurochemicals in pts with traumatic brain injury. This study was conducted to evaluate the use of MD to define the time course of intratumoral drug concentrations in pts with high grade gliomas (HGG) receiving systemic chemotherapy. Methods: MD catheters were placed in residual HGG following tumor debulking and infused with Ringer’s solution at 1 μL/min. MD probe location and integrity of the blood brain barrier (BBB) in adjacent tissue were determined by fused MRI/CT. Highdose (12g/m2) methotrexate (MTX), was given as a 4 h iv infusion the next day. MTX was measured in plasma and dialysate samples, collected at 30 min intervals from 1 h before to 24 h after dosing, with an LC/MS assay. Results: Six pts have been enrolled without any adverse events attributed to the MD catheter. Adequate pharmacokinetics (PK) were obtained in 4/6pts. MTX plasma pharmacokinetics (PK) were very consistent between the 4 evaluable pts and similar to published data. Time courses of the uncorrected MTX concentration in extracellular fluid (CECF) exhibited two distinctly different kinetic profiles. For 2pts in whom the MD probe resided within contrast enhancing tumor, CECF increased and decreased in parallel with drug levels in plasma, with a peak CECF of 189 ± 6 μM, an apparent elimination half-life in ECF of 4.44 ± 0.07 h, and an ECF/plasma AUCratio of 0.13 ± 0.01. The other 2pts had a much lower peak CECF (10.4 ± 0.4 μM) and AUC ratio (0.028 ± 0.020), with a more prolonged ECF half-life (11.4 ± 4.5 h). Fused images from 2 of these pts showed that the MD probe was located in nonenhancing tissue. Conclusions: MD is a clinically practical technique to monitor the distribution of systemically administered drugs to brain tumors in pts. It has the capability to elucidate variations in kinetic behavior that are consistent with regional differences in BBB integrity. Appropriate interpretation of data from MD studies to evaluate the distribution of investigational new drugs into brain tumors necessarily requires radiographic determination of the region of the tumor into which the probe has been placed. No significant financial relationships to disclose.

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