scholarly journals Phase I trial of convection-enhanced delivery of nimustine hydrochloride (ACNU) for brainstem recurrent glioma

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Ryuta Saito ◽  
Masayuki Kanamori ◽  
Yukihiko Sonoda ◽  
Yoji Yamashita ◽  
Kenichi Nagamatsu ◽  
...  
Keyword(s):  
Phase I ◽  
Real Time ◽  
Phase I Trial ◽  
Treatment Options ◽  
Drug Distribution ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Real Time Monitoring ◽  
Convection Enhanced Delivery ◽  
Dose Concentration ◽  
Nimustine Hydrochloride

Abstract Background Treatment options for patients suffering brainstem gliomas are quite limited as surgery is not an option against intrinsic tumors at brainstem and chemotherapy generally failed to demonstrate its efficacy. Intracerebral convection-enhanced delivery (CED) is a novel approach for administering chemotherapy to patients with brain tumors. We present the results of phase I trial of CED of nimustine hydrochloride (ACNU), designed to determine the maximum tolerable concentration of ACNU, for patients with recurrent brainstem gliomas. Methods Sixteen patients, aged 3–81 years old, suffering from recurrent brainstem gliomas, including diffuse intrinsic pontine glioma patients as well as patients with recurrent gliomas that originated from non-brainstem sites, were enrolled in this trial between February 2011 and April 2016. The dose/concentration escalation trial included 3 dose/concentration groups (0.25, 0.5, and 0.75 mg/mL, all at 7 mL) to determine the safety and tolerability of CED of ACNU. Real-time monitoring of drug distribution was performed by mixing gadolinium-tetraazacyclododecanetetraacetic acid (Gd-DOTA) in the infusion solution. CED of ACNU was given in combination with oral or intravenous temozolomide chemotherapy. Results CED of ACNU demonstrated antitumor activity, as assessed by radiographic changes and prolonged overall survival. The recommended dosage was 0.75 mg/mL. Drug-associated toxicity was minimal. Conclusions Intracerebral CED of ACNU under real-time monitoring of drug distribution, in combination with systemic temozolomide, was well tolerated among patients with recurrent brainstem gliomas. The safety and efficacy observed suggest the clinical benefits of this strategy against this devastating disease. Based on this phase I study, further clinical development of ACNU is warranted.

Safety and feasibility of convection-enhanced delivery of nimustine hydrochloride co-infused with free gadolinium for real-time monitoring in the primate brain

2012 ◽  
Vol 34 (6) ◽  
pp. 581-587 ◽  
Author(s):  
Shin-ichiro Sugiyama ◽  
Ryuta Saito ◽  
Taigen Nakamura ◽  
Yoji Yamashita ◽  
Michiko Yokosawa ◽  
...  
Keyword(s):  
Real Time ◽  
Real Time Monitoring ◽  
Convection Enhanced Delivery ◽  
Primate Brain ◽  
Nimustine Hydrochloride

scholarly journals DIPG-40. TARGETING MASTER REGULATOR DEPENDENCIES IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii294-iii295
Author(s):  
Jovana Pavisic ◽  
Chankrit Sethi ◽  
Chris Jones ◽  
Stergios Zacharoulis ◽  
Andrea Califano
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Treatment Options ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Low Grade ◽  
Precision Oncology ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
Master Regulator

Abstract Diffuse intrinsic pontine glioma (DIPG) remains a fatal disease with no effective drugs to date. Mutation-based precision oncology approaches are limited by lack of targetable mutations and genetic heterogeneity. We leveraged systems biology methodologies to discover common targetable disease drivers—master regulator proteins (MRs)—in DIPG to expand treatment options. Using the metaVIPER algorithm, we interrogated an integrated low grade glioma and GBM gene regulatory network with 31 DIPG-gene expression signatures to identify tumor-specific MRs by differential expression of their transcriptional targets. Unsupervised clustering identified MR signatures of upregulated activity in RRM2/TOP2A in 13 patients, CD3D in 5 patients, and MMP7, TACSTD2, RAC2 and SLC15A1/SLC34A2 in individual patients, all of which can be targeted. Notably, intratumoral administration of etoposide by convection enhanced delivery was effective in murine proneural gliomas in which TOP2 was identified as a MR while RRM2—targetable by drugs such as cladribine—has been shown to be a positive regulator of glioma progression whose knock-down inhibits tumor growth. We also prioritized drugs by their ability to reverse MR-activity signatures using a large drug-perturbation database. Patients clustered by predicted drug sensitivities with distinct groups of tumors predicted to respond to proteasome inhibitors, Thiotepa or Volasertib all of which have early evidence in treating gliomas. We will refine this analysis in a multi-institutional study of >100 patient gene expression profiles to define MR signatures driving known biological/molecular disease subtypes, use DIPG cell lines recapitulating common MR architectures to optimize therapy prioritization, and validate our findings in vivo.

scholarly journals Influence of an intratumoral cyst on drug distribution by convection-enhanced delivery: case report

2017 ◽  
Vol 20 (3) ◽  
pp. 256-260 ◽  
Author(s):  
Iryna Ivasyk ◽  
Peter F. Morgenstern ◽  
Eva Wembacher-Schroeder ◽  
Mark M. Souweidane
Keyword(s):  
Drug Distribution ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Positive Pressure ◽  
Target Point ◽  
Convection Enhanced Delivery ◽  
Clinical Trial Registration ◽  
Software Analysis ◽  
Catheter Tip ◽  
Cystic Cavity ◽  
Brainstem Tumors

Convection-enhanced delivery (CED) uses positive pressure to induce convective flow of molecules and maximize drug distribution. Concerns have been raised about the effect of cystic structures on uniform drug distribution with CED. The authors describe the case of a patient with a diffuse intrinsic pontine glioma (DIPG) with a large cyst and examine its effect on drug distribution after CED with a radiolabeled antibody. The patient was treated according to protocol with CED of 124I-8H9 to the pons for nonprogressive DIPG after radiation therapy as part of a Phase I trial (clinical trial registration no. NCT01502917, clinicaltrials.gov). Care was taken to avoid the cystic cavity in the planned catheter track and target point. Co-infusion with Gd-DTPA was performed to assess drug distribution. Infusate distribution was examined by MRI immediately following infusion and analyzed using iPlan Flow software. Analysis of postinfusion MR images demonstrated convective distribution around the catheter tip and an elongated configuration of drug distribution, consistent with the superoinferior corticospinal fiber orientation in the brainstem. This indicates that the catheter was functioning and a pressure gradient was established. No infusate entry into the cystic region could be identified on T2-weighted FLAIR or T1-weighted images. The effects of ependymal and pial surfaces on drug delivery using CED in brainstem tumors remain controversial. Drug distribution is a critical component of effective application of CED to neurosurgical lesions. This case suggests that cyst cavities may not always behave as fluid “sinks” for drug distribution. The authors observed that infusate was not lost into the cyst cavity, suggesting that lesions with cystic components can be treated by CED without significant alterations to target and infusion planning.

PI-REAL: A study of informed consent (IC) communication in real-time during phase I clinical trial encounters.

2015 ◽  
Vol 33 (29_suppl) ◽  
pp. 22-22
Author(s):  
Manish Sharma ◽  
Fay J. Hlubocky ◽  
Mark J. Ratain ◽  
Mark Siegler ◽  
Christopher Daugherty
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Real Time ◽  
Phase I Trial ◽  
Phase I Clinical Trial ◽  
Research Purpose ◽  
Median Income ◽  
Phase I Clinical Trials ◽  
Verbal Skills ◽  
Video Recordings

22 Background: Advanced cancer patients (ACP) in phase I clinical trials are unable to recall significant elements of IC, yet the actual verbal and non-verbal content of trial discussion between oncology fellows and ACP consenting in real time to such trials has not been well described. Methods: Phase I Communication in Real Time Fellow-ACP Encounters (PI-REAL) study is an evidence-based intervention designed to improve communication about phase I clinical trial IC. ACP completed follow-up questionnaires after new patient visits to assess understanding of IC elements, such as research purpose. Video recordings were analyzed using CanCode for verbal and non-verbal skills associated with IC elements. Results: To date, 61 ACP-fellow clinical encounter video recordings were available for analysis. Average length of encounters: 45.4 min (range: 5.7-87.8 min). ACP demographics included: median age 60y (33-83); 55% male; 89% Caucasian; 55% median income > $60,000. Fellows were coded as verbally disclosing: 1. Purpose of phase I trial as dose-determining in 49% of encounters; 2. Physical risks of trial in 75% of encounters; 3. Potential benefits (e.g. improved QOL) gained by ACP participation in trial in 70% of encounters; 4. Alternatives to trial entry (e.g. other trials, palliative/supportive care) in 55% of encounters. A significant association existedbetween coded fellow empathic statements and ACP subsequently recalling the purpose of the trial as dose-determining, with 72% of subjects who heard empathic statements identifying “dosage” compared to 10% of subjects who did not (72% v. 10%, p < 0.05). Regarding non-verbal skills, fellows: leaned toward ACP in 64% of encounters; observed ACP face directly in 72% of encounters; had relaxed body posture in 55% of encounters; and displayed responsive facial expressions in 77% of encounters. Conclusions: Empathic statements by fellows appear to be associated with improved ACP understanding of Phase I trial research purpose as dose-determining. Additional encounters continue to undergo video recording and analysis.

A phase I study of convection-enhanced delivery of nanoliposomal irinotecan using real-time imaging in patients with recurrent high grade glioma.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. TPS2081-TPS2081
Author(s):  
Nicholas A. Butowski ◽  
Seunggu Han ◽  
Jennie Webster Taylor ◽  
Manish K. Aghi ◽  
Michael Prados ◽  
...  
Keyword(s):  
Phase I ◽  
Real Time ◽  
Phase I Study ◽  
High Grade Glioma ◽  
High Grade ◽  
Convection Enhanced Delivery ◽  
Real Time Imaging ◽  
Nanoliposomal Irinotecan

scholarly journals Phase I trial of convection-enhanced delivery of IL13-Pseudomonas toxin in children with diffuse intrinsic pontine glioma

2019 ◽  
Vol 23 (3) ◽  
pp. 333-342 ◽  
Author(s):  
John D. Heiss ◽  
Aria Jamshidi ◽  
Smit Shah ◽  
Staci Martin ◽  
Pamela L. Wolters ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Disease Progression ◽  
Performance Status ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
Antitumor Effects ◽  
Radiographic Findings ◽  
Long Term Treatment

OBJECTIVEIn this clinical trial report, the authors analyze safety and infusion distribution of IL13-Pseudomonas exotoxin, an antitumor chimeric molecule, administered via intratumoral convection enhanced delivery (CED) in pediatric patients with diffuse intrinsic pontine glioma (DIPG).METHODSThis was a Phase I single-institution, open-label, dose-escalation, safety and tolerability study of IL13-PE38QQR infused via single-catheter CED into 5 pediatric DIPG patients. IL13-PE38QQR was administered to regions of tumor selected by radiographic findings. Two escalating dose levels were evaluated: 0.125 µg/mL in cohort 1 and 0.25 µg/mL in cohort 2. Real-time MRI was performed during intratumoral infusions, and MRI and MR spectroscopy were performed before and after the infusions. Clinical evaluations, including parent-reported quality of life (QOL), were assessed at baseline and 4 weeks post-infusion.RESULTSDirect infusion of brainstem tumor with IL13-PE using the CED technique in patients with DIPG produced temporary arrest of disease progression in 2 of 5 patients, both of whom subsequently received a second infusion. All 5 patients showed signs of disease progression by 12 weeks after initial infusion. Two patients experienced transient cranial nerve deficits and lethargy after infusion, and these deficits resolved with corticosteroid treatment in both cases. No patient had radiographic evidence of acute or long-term treatment toxicity. Parent-reported QOL was consistent with medical outcomes.CONCLUSIONSEven though IL13-PE delivered by CED did not reach the entire MRI-defined tumor volume in any patient, short-term radiographic antitumor effects were observed in 2 of the 5 patients treated. The patients’ performance status did not improve. Drug delivery using multiple catheters may produce improved outcomes.Clinical trial registration no.: NCT00088061 (clinicaltrials.gov)

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 Effect of ependymal and pial surfaces on convectionenhanced delivery

2008 ◽  
Vol 109 (3) ◽  
pp. 547-552 ◽  
Author(s):  
Jay Jagannathan ◽  
Stuart Walbridge ◽  
John A. Butman ◽  
Edward H. Oldfield ◽  
Russell R. Lonser
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Mr Imaging ◽  
Real Time ◽  
Drug Distribution ◽  
Leading Edge ◽  
Volume Of Distribution ◽  
Clinical Effects ◽  
Convection Enhanced Delivery ◽  
Pia Mater

Object Convection-enhanced delivery (CED) is increasingly used to investigate new treatments for central nervous system disorders. Although the properties of CED are well established in normal gray and white matter central nervous system structures, the effects on drug distribution imposed by ependymal and pial surfaces are not precisely defined. To determine the effect of these anatomical boundaries on CED, the authors infused low MW and high MW tracers for MR imaging near ependymal (periventricular) and pial (pericisternal) surfaces. Methods Five primates underwent CED of Gd-diethylenetriamine pentaacetic acid (Gd-DTPA; MW 590 D) or Gd-bound albumin (Gd-albumin; MW 72,000 D) during serial real-time MR imaging (FLAIR and T1-weighted sequences). Periventricular (caudate) infusions were performed unilaterally in 1 animal (volume of infusion [Vi] 57 μl) and bilaterally in 1 animal with Gd-DTPA (Vi = 40 μl on each side), and bilaterally in 1 animal with Gd-albumin (Vi = 80 μl on each side). Pericisternal infusions were performed in 2 animals with Gd-DTPA (Vi = 190 μl) or with Gd-albumin (Vi = 185 μl) (1 animal each). Clinical effects, MR imaging, and histology were analyzed. Results Large regions of the brain and brainstem were perfused with both tracers. Intraparenchymal distribution was successfully tracked in real time by using T1-weighted MR imaging. During infusion, the volume of distribution (Vd) increased linearly (R2 = 0.98) with periventricular (mean Vd/Vi ratio ± standard deviation; 4.5 ± 0.5) and pericisternal (5.2 ± 0.3) Vi, but did so only until the leading edge of distribution reached the ependymal or pial surfaces, respectively. After the infusate reached either surface, the Vd/Vi decreased significantly (ependyma 2.9 ± 0.8, pia mater 3.6 ± 1.0; p < 0.05) and infusate entry into the ventricular or cisternal cerebrospinal fluid (CSF) was identified on FLAIR but not on T1-weighted MR images. Conclusions Ependymal and pial boundaries are permeable to small and large molecules delivered interstitially by convection. Once infusate reaches these surfaces, a portion enters the adjacent ventricular or cisternal CSF and the tissue Vd/Vi ratio decreases. Although T1-weighted MR imaging is best for tracking intraparenchymal infusate distribution, FLAIR MR imaging is the most sensitive and accurate for detecting entry of Gd-labeled imaging compounds into CSF during CED.

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