Phase 1 Safety, Pharmacokinetics, and Fluorescence Imaging Study of Tozuleristide (BLZ-100) in Adults With Newly Diagnosed or Recurrent Gliomas

Neurosurgery ◽  
2019 ◽  
Vol 85 (4) ◽  
pp. E641-E649 ◽  
Author(s):  
Chirag G Patil ◽  
David G Walker ◽  
Dennis M Miller ◽  
Pramod Butte ◽  
Beth Morrison ◽  
...  
Keyword(s):  
Fluorescence Imaging ◽  
Near Infrared ◽  
Infrared Imaging ◽  
Ex Vivo ◽  
Phase 1 ◽  
Fluorescence Signal ◽  
Low Grade ◽  
Lower Grade ◽  
High Grade ◽  
Dose Escalation Study

AbstractBACKGROUNDFluorescence-guided surgery (FGS) can improve extent of resection in gliomas. Tozuleristide (BLZ-100), a near-infrared imaging agent composed of the peptide chlorotoxin and a near-infrared fluorophore indocyanine green, is a candidate molecule for FGS of glioma and other tumor types.OBJECTIVETo perform a phase 1 dose-escalation study to characterize the safety, pharmacokinetics, and fluorescence imaging of tozuleristide in adults with suspected glioma.METHODSPatients received a single intravenous dose of tozuleristide 3 to 29 h before surgery. Fluorescence images of tumor and cavity in Situ before and after resection and of excised tissue ex Vivo were acquired, along with safety and pharmacokinetic measures.RESULTSA total of 17 subjects received doses between 3 and 30 mg. No dose-limiting toxicity was observed, and no reported adverse events were considered related to tozuleristide. At doses of 9 mg and above, the terminal serum half-life for tozuleristide was approximately 30 min. Fluorescence signal was detected in both high- and low-grade glial tumors, with high-grade tumors generally showing greater fluorescence intensity compared to lower grade tumors. In high-grade tumors, signal intensity increased with increased dose levels of tozuleristide, regardless of the time of dosing relative to surgery.CONCLUSIONThese results support the safety of tozuleristide at doses up to 30 mg and suggest that tozuleristide imaging may be useful for FGS of gliomas.

A phase I study to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activities of daily oral BAL101553, a novel tumor checkpoint controller (TCC) in adult patients with progressive or recurrent glioblastoma (GBM) or high-grade glioma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2601-TPS2601
Author(s):  
Alvaro Henrique Ingles Garces ◽  
Elizabeth R. Plummer ◽  
Juanita Suzanne Lopez ◽  
Rebecca Sophie Kristeleit ◽  
Julie MacDonald ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Dose Escalation ◽  
Spindle Assembly Checkpoint ◽  
Phase 1 ◽  
High Grade Glioma ◽  
Low Grade ◽  
High Grade ◽  
Tumor Cell Death ◽  
Antitumor Activities ◽  
Dose Escalation Study

TPS2601 Background: BAL101553 (prodrug of BAL27862) is a novel TCC that promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 is a lipophilic, small molecule (MW 387) shown in rats to penetrate the brain (1:1 plasma ratio) and has shown promising antitumor activity in orthotopic preclinical models of GBM as monotherapy or in combination with radiotherapy (RT) with/without chemotherapy. In a completed Phase 1 study with 2-h IV infusions (Days 1, 8, 15, q28d, NCT01397929 , CDI-CS-001, Lopez et al. J Clin Oncol 34, 2016 suppl; 2525), dose-limiting vascular effects were observed and appeared Cmax related. Preclinical data suggest that antiproliferative effects of BAL101553/27862 are driven by exposure (AUC); thus vascular toxicity and antitumor activity are mediated by different PK drivers. In this ongoing study (NCT02490800, CDI-CS-002), daily oral BAL101553 was initially examined in solid-tumor patients; no vascular toxicities were observed at doses up to the MAD of 30 mg QD. Given this absence, the study was amended to enroll separate cohorts of patients with progressive or recurrent GBM or high-grade glioma. Methods: This is an ongoing multicenter, open-label, Phase 1 dose-escalation study using a 3+3 design to determine the MTD, characterize dose-limiting toxicities and assess the PK, PD and antitumor activities of daily oral administration of BAL101553 in consecutive 28-day cycles at a starting dose of 8 mg QD. Patients with histologically-confirmed GBM or high-grade glioma, with progressive or recurrent disease after prior RT with/without chemotherapy, are eligible for enrollment. This includes patients with histologically-confirmed low-grade glioma with unequivocal evidence by imaging of transformation to high-grade glioma. Adverse events are assessed using CTCAEv4; tumor response by RANO (every 2 cycles). The dose escalation allows for doubling of dose levels depending on observed toxicities. PD assessments include circulating tumor cells. PK profiles are assessed throughout the first two treatment cycles. Clinical trial information: NCT02490800.

scholarly journals Real-time Visualization of Breast Carcinoma in Pathology Specimens From Patients Receiving Fluorescent Tumor-Marking Agent Tozuleristide

2018 ◽  
Vol 143 (9) ◽  
pp. 1076-1083 ◽  
Author(s):  
Suzanne M. Dintzis ◽  
Stacey Hansen ◽  
Kristi M. Harrington ◽  
Lennart C. Tan ◽  
Dennis M. Miller ◽  
...  
Keyword(s):  
Breast Carcinoma ◽  
Real Time ◽  
Near Infrared ◽  
Infrared Imaging ◽  
Ex Vivo ◽  
Clinical Pathology ◽  
Low Grade ◽  
Imaging Device ◽  
Invasive Carcinomas

Context.— Resection of breast carcinoma with adequate margins reduces the risk of local recurrence and reoperation. Tozuleristide (BLZ-100) is an investigational peptide-fluorophore agent that may aid in intraoperative tumor detection and margin assessment. In this study, fluorescence imaging was conducted ex vivo on gross breast pathology specimens. Objectives.— To determine the potential of tozuleristide to detect breast carcinoma in fresh pathology specimens and the feasibility of fluorescence-guided intraoperative pathology assessment of surgical margins. Design.— Twenty-three patients received an intravenous bolus dose of 6 or 12 mg of tozuleristide at least 1 hour before surgery. Fifteen lumpectomy and 12 mastectomy specimens were evaluated for fluorescence by the site's clinical pathology staff using the SIRIS, an investigational near-infrared imaging device. The breast tissue was then processed per usual procedures. Fluorescent patterns were correlated with the corresponding hematoxylin-eosin–stained sections. Clinical pathology reports were used to correlate fluorescent signal to grade, histotype, prognostic marker status, and margin measurements. Results.— Tozuleristide fluorescence was readily observed in invasive and in situ breast carcinoma specimens. Most invasive carcinomas were bright and focal, whereas in situ lesions demonstrated a less intense, more diffuse pattern. Tozuleristide was detected in ductal and lobular carcinomas with a similar fluorescent pattern. Fluorescence was detected in high- and low-grade lesions, and molecular marker/hormone receptor status did not affect signal. Fluorescence could be used to identify the relationship of carcinoma to margins intraoperatively. Conclusions.— Tumor targeting with tozuleristide allowed visual real-time distinction between pathologically confirmed breast carcinoma and normal tissue.

A phase II/III randomized, blinded study of tozuleristide for fluorescence imaging detection during neurosurgical resection of pediatric primary central nervous system (CNS) tumors: PNOC012 (Pacific Pediatric Neuro-oncology Consortium).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS2575-TPS2575
Author(s):  
Sarah Leary ◽  
Jason E. Blatt ◽  
Alan R. Cohen ◽  
Kenneth J. Cohen ◽  
Bonnie Cole ◽  
...  
Keyword(s):  
Fluorescence Imaging ◽  
Near Infrared ◽  
Tumor Tissue ◽  
Phase 1 ◽  
Tumor Resection ◽  
Fluorescent Imaging ◽  
Low Grade ◽  
Primary Efficacy ◽  
Imaging Device ◽  
Patient Reported

TPS2575 Background: Tozuleristide (also known as BLZ-100 or Tumor Paint) is a fluorescent imaging drug designed to specifically label and accumulate in tumor tissue, thus enabling more precise surgical tumor resection intraoperatively. Tozuleristide achieves tumor targeting through the peptide portion of the molecule, a modified chlorotoxin peptide, and its imaging properties from a coupled near-infrared fluorescent dye, an indocyanine green. Tozuleristide has been studied in 4 Phase 1 studies, including a trial in pediatric brain cancer subjects. No tozuleristide SAEs or dose limiting toxicity were observed in the 97 subjects treated in the Phase 1 program at doses up to 30 mg in adults or 17.3 mg/m2 in pediatrics (Hansen S et al, WMIC 2018, P196). Eighty percent of pediatric subjects receiving tozuleristide had tumors considered fluorescence positive, including high and low grade glioma, ependymoma, and medulloblastoma. Methods: This study randomizes subjects in a 1:10 ratio to standard of care or tozuleristide arms. The primary efficacy objectives and endpoints are based on equivocal regions of tissue encountered in surgery. Prior to fluorescence assessment, the surgeon assesses the suspected nature of the tissue (more likely tumor/less likely tumor). Tissue specimens of equivocal regions are collected for blinded central pathology assessment. Sensitivity and specificity of the surgeon’s designation, fluorescence assessment, and ratios of surgeon to fluorescence assessments comprise the primary efficacy analyses. Tozuleristide is given as an IV bolus dose of 15 mg/m2 to pediatric subjects 1 to 36 hours prior to surgery. Subjects must have a MRI documented lesion consistent with a CNS tumor for which resection is planned. Measures of safety include adverse events, laboratory measures of hematology, liver and kidney function and changes in vital signs and ECGs. Pharmacokinetic blood samples are collected up to 3 hr post dose. Fluorescence imaging is assessed during surgery using an investigational “Canvas System” imaging device attached to a surgical microscope. Collected pathology specimens will also be subjected to further genetic, molecular and pathology studies, including fluorescence assessment of frozen tissue sections. SAEs and patient reported outcomes are collected for 3 months. The SMC for the study last reviewed the data for this study in July 2019 and recommended the trial continue as planned. Clinical trial information: NCT03579602 .

scholarly journals Multicellular ‘hotspots’ harbour high-grade potential in lower-grade gliomas

2021 ◽  
Author(s):  
Alastair J Kirby ◽  
José P Lavrador ◽  
Istvan Bodi ◽  
Francesco Vergani ◽  
Ranjeev Bhangoo ◽  
...  
Keyword(s):  
Human Brain ◽  
Brain Tissue ◽  
Aminolevulinic Acid ◽  
Ex Vivo ◽  
Brain Slices ◽  
Glioma Cells ◽  
Malignant Progression ◽  
Lower Grade ◽  
High Grade ◽  
Human Brain Tissue

Abstract Background Lower-grade gliomas may be indolent for many years before developing malignant behaviour. The reasons mechanisms underlying malignant progression remain unclear. Methods We collected blocks of live human brain tissue donated by people undergoing glioma resection. The tissue blocks extended through the peritumoral cortex and into the glioma. The living human brain tissue was cut into ex vivo brain slices and bathed in 5-aminolevulinic acid (5-ALA). High-grade glioma cells avidly take up 5-aminolevulinic acid (5-ALA) and accumulate high levels of the fluorescent metabolite, Protoporphyrin IX (PpIX). We exploited the PpIX fluorescence emitted by higher-grade glioma cells to investigate the earliest stages of malignant progression in lower-grade gliomas. Results We found sparsely-distributed ‘hot-spots’ of PpIX-positive cells in living lower-grade glioma tissue. Glioma cells and endothelial cells formed part of the PpIX hotspots. Glioma cells in PpIX hotspots were IDH1 mutant and expressed nestin suggesting they had acquired stem-like properties. Spatial analysis with 5-ALA conjugated quantum dots indicated that these glioma cells replicated adjacent to blood vessels. PpIX hotspots formed in the absence of angiogenesis. Conclusion Our data show that PpIX hotspots represent microdomains of cells with high-grade potential within lower-grade gliomas and identify locations where malignant progression could start.

scholarly journals A Molecularly Targeted Intraoperative Near-Infrared Fluorescence Imaging Agent for High-Grade Serous Ovarian Cancer

2020 ◽  
Vol 17 (8) ◽  
pp. 3140-3147 ◽  
Author(s):  
Kimberly Fung ◽  
Sai Kiran Sharma ◽  
Outi Keinänen ◽  
Kara Long Roche ◽  
Jason S. Lewis ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Fluorescence Imaging ◽  
Near Infrared ◽  
Imaging Agent ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Near Infrared Fluorescence ◽  
Near Infrared Fluorescence Imaging

scholarly journals Evaluation to Differentiate between Tumor Lesions and the Parenchyma in Partial Nephrectomies for Renal Tumors Based on Quantitative Fluorescence Imaging Using Indocyanine Green Dye

2019 ◽  
Vol 13 (2) ◽  
pp. 74-81
Author(s):  
Norihito Soga ◽  
Akihito Inoko ◽  
Jun Furusawa ◽  
Yuji Ogura
Keyword(s):  
Indocyanine Green ◽  
Success Rate ◽  
Fluorescence Imaging ◽  
Partial Nephrectomy ◽  
Near Infrared ◽  
Clear Cell ◽  
Ex Vivo ◽  
Renal Tumors ◽  
Contrast Imaging ◽  
Malignant Lesions

Introduction: Near-infrared fluorescence imaging with indocyanine green is a useful tool during partial nephrectomy. Because an accurate method for judging hasn't been established yet, the success rate may be slightly different and inconsistent. Materials and Methods: A total of 21 cases with suspected renal cancers who had undergone a partial nephrectomy were enrolled. We examined differences in the success rate between malignant lesions and the parenchyma by quantifying fluorescence in the pre-resection and ex vivo phases. Results: Pre-resection imaging showed a significant degradation of fluorescence in the focused lesion in 76.2% (16/21) of cases. A significant degradation was observed in 73.7% (14/19) of the total malignant lesions, 70.5% (12/17) of cases with a clear cell lesion, 100% (2/2) of cases with non-clear cell lesions, and 100% (2/2) of benign angiomyolipomas. In contrast, imaging of the ex vivo resected specimens showed a significant degradation in fluorescence of the focused lesions in 85.7% (18/21) of cases. A significantly degradation was observed in 84.2% (16/19) of the total malignant lesions, 82.3% (14/17) of cases with a clear cell lesion, 100% (2/2) of cases with non-clear cell lesions, and 100% (2/2) of benign angiomyolipomas. Conclusion: We firstly evaluated the efficacy of quantitative indocyanine green-based fluorescence as an objective method.

scholarly journals Detection of early neoplasia in Barrett’s esophagus using lectin-based near-infrared imaging: an ex vivo study on human tissue

Endoscopy ◽  
2018 ◽  
Vol 50 (06) ◽  
pp. 618-625 ◽  
Author(s):  
André Neves ◽  
Massimiliano Di Pietro ◽  
Maria O’Donovan ◽  
Dale Waterhouse ◽  
Sarah Bohndiek ◽  
...  
Keyword(s):  
Barrett’S Esophagus ◽  
Barrett's Esophagus ◽  
Near Infrared ◽  
Infrared Imaging ◽  
Ex Vivo ◽  
Sampling Error ◽  
Nir Light ◽  
Nir Imaging ◽  
Nir Fluorescence ◽  
Nir Dye

Abstract Background and study aims Endoscopic surveillance for Barrett’s esophagus (BE) is limited by long procedure times and sampling error. Near-infrared (NIR) fluorescence imaging minimizes tissue autofluorescence and optical scattering. We assessed the feasibility of a topically applied NIR dye-labeled lectin for the detection of early neoplasia in BE in an ex vivo setting. Methods Consecutive patients undergoing endoscopic mucosal resection (EMR) for BE-related early neoplasia were recruited. Freshly collected EMR specimens were sprayed at the bedside with fluorescent lectin and then imaged. Punch biopsies were collected from each EMR under NIR light guidance. We compared the fluorescence intensity from dysplastic and nondysplastic areas within EMRs and from punch biopsies with different histological grades. Results 29 EMR specimens were included from 17 patients. A significantly lower fluorescence was found for dysplastic regions across whole EMR specimens (P < 0.001). We found a 41 % reduction in the fluorescence of dysplastic compared to nondysplastic punch biopsies (P < 0.001), with a sensitivity and specificity for dysplasia detection of 80 % and 82.9 %, respectively. Conclusion Lectin-based NIR imaging can differentiate dysplastic from nondysplastic Barrett’s mucosa ex vivo.

scholarly journals Intraoperative Near-Infrared Fluorescence Imaging With Second-Window Indocyanine-Green Offers Accurate and Real-Time Correction for Brain Shift and Anatomic Inconsistencies in Framless Neuronavigation

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Steve Sungwon Cho ◽  
Ashwin G Ramayya ◽  
Clare W Teng ◽  
Steven Brem ◽  
Sunil Singhal ◽  
...  
Keyword(s):  
Real Time ◽  
Fluorescence Imaging ◽  
Near Infrared ◽  
Infrared Imaging ◽  
P Value ◽  
Brain Shift ◽  
Intracranial Tumors ◽  
Near Infrared Imaging ◽  
Near Infrared Fluorescence ◽  
Near Infrared Fluorescence Imaging

Abstract INTRODUCTION Neuronavigation allows neurosurgeons to localize intracranial structures in 3D space and has been shown to have positive impacts on patient survival in neuro-oncology surgery. However, its major limitation is the intraoperative brain-shift phenomenon, in which the brain moves during surgery due to physical, surgical, and/or biological factors, invalidating the preoperative registration and leading to inaccuracies in the cranium. One reliable way to account for brain-shift intraoperatively may be to use tumor-targeting near-infrared fluorophores, such as ICG accumulating in neoplastic tissue (ie, Second-Window ICG), which offers real-time visualization of tumors through normal cortex and dura. METHODS Patients undergoing craniotomy for primary resection of intracranial tumors were enrolled under an ongoing clinical trial investigating the efficacy of SWIG. For this analysis, retrospective data were collected on patients in whom neuronavigation was used to plan the craniotomy in such a way as to place the tumor in the center of the craniotomy (ie, parasagittal tumors, skull-base tumors, and large/asymmetrical tumors were excluded). During surgery, near-infrared imaging was performed before and after durotomy to localize the gross tumor. Image analysis was performed to measure the deviation between the craniotomy center and the center of the tumor as seen with near-infrared fluorescence. RESULTS A total of 63 patients (24 high-grade-gliomas, 12 meningiomas, 25 metastases, 2 others) were included in this preliminary analysis. Neuronavigation demonstrated a median deviation of 22.4% (range 7.7%-44.4%) relative to craniotomy size. Patient position was a significant predictor of neuronavigation inaccuracy, with the prone position having significantly higher inaccuracy (28.5 ± 8.8%) compared to the supine (19.3 ± 9.2%, P-value = .015) or the lateral (17.9 ± 6.6%, P-value = .012) positions. Additionally, the neuronavigation device used and postgraduate training level of the residents performing the registration trended towards significance on multivariate analysis. In contrast, near-infrared fluorescence perfectly delineated the tumor in all cases. CONCLUSION We demonstrate that near-infrared fluorescence imaging offers more accurate localization of intracranial tumors compared to frameless neuronavigation. Near-infrared imaging could potentially be used to adjust neuronavigation registrations intraoperatively to enhance accuracy. Further prospective studies with distance measurements could better explore this potential benefit of intraoperative near-infrared imaging.

Rhenium and technetium-complexed silicon rhodamines as near-infrared imaging probes for bimodal SPECT- and optical imaging

2020 ◽  
Vol 49 (22) ◽  
pp. 7294-7298 ◽  
Author(s):  
Thines Kanagasundaram ◽  
Carsten S. Kramer ◽  
Eszter Boros ◽  
Klaus Kopka
Keyword(s):  
Optical Imaging ◽  
Fluorescence Imaging ◽  
Near Infrared ◽  
Infrared Imaging ◽  
Near Infrared Imaging ◽  
Near Infrared Fluorescence ◽  
Technetium 99M ◽  
Imaging Probes ◽  
Near Infrared Fluorescence Imaging

The first technetium-99m tricarbonyl core labelled fluorescent Si-rhodamine and its rhenium analogue for bimodal SPECT- and near-infrared fluorescence imaging is presented.

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