First-in-human CAN-3110 (ICP-34.5 expressing HSV-1 oncolytic virus) in patients with recurrent high-grade glioma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2009-2009
Author(s):  
E. Antonio Chiocca ◽  
Isaac Solomon ◽  
Hiroshi Nakashima ◽  
Sean Edward Lawler ◽  
Daniel Triggs ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Phase 1 ◽  
High Grade Glioma ◽  
Oncolytic Viruses ◽  
Recurrent Glioma ◽  
Experimental Medicine ◽  
High Grade ◽  
Entire Study ◽  
Hsv 1

2009 Background: Recurrent glioma patients have few therapeutic options and an expected survival of only 7 to 10 months. New treatments to improve the prognosis of this patient population are a dire medical need. Oncolytic viruses (OVs) are emerging as important new agents for cancer treatment. The first FDA approved OV was talimogene laherparepvec (Imlygic, T-Vec) for treatment of melanoma. T-Vec, as most other clinical HSV-1 based OVs, is deleted in the ICP34.5 gene, which is responsible for HSV-1 neurovirulence. However, deletion of ICP34.5 also impedes efficient viral replication. CAN-3110 (rQNestin34.5v2) maintains a copy of the HSV1 ICP34.5 gene under transcriptional control of the tumor-specific promoter for nestin to drive robust tumor-selective replication. CAN-3110 replicates in malignant glioma cells far above levels seen with ICP34.5 deleted viruses. This potency also created the hypothetical risk for increased neurovirulence, thus the regulatory advice to conduct a cautious nine-dose-level Phase-1 dose escalation study in patients with recurrent high-grade glioma (HGG). Methods: From September 2017 to February 2020, thirty patients with biopsy-confirmed recurrent high-grade glioma were treated in an open label clinical trial. Patients with multifocal, multicentric, tumors larger than 5 cm, and tumors that had recurred multiple times were eligible. All patients received best standard of care treatments as indicated by their physician. CAN-3110 was injected intratumorally starting at 1x106 plaque forming units (pfu) and dose-escalating (3+3 design) by half log increments up to 1x1010 pfu. Tissue (when possible) and blood samples were obtained before and during treatment for experimental medicine analyses. Results: CAN-3110 was well tolerated with no dose limiting toxicity observed. The initial tissue diagnosis of the recurrent tumor for the 30 subjects was 26 glioblastoma, 3 anaplastic oligodendroglioma, and 1 anaplastic astrocytoma. The median overall survival (mOS) of the entire study group is 13.25 months. Post-treatment tissue is available for 18/30 subjects and revealed persistence of HSV antigen and CD8+ T cell infiltrates. Additional response, immunologic (including T cell receptor repertoire), transcriptomic and single cell RNA sequencing analyses are ongoing. Conclusions: Administration of CAN-3110 into recurrent glioma was well tolerated without evidence of ICP34.5-induced encephalitis/meningitis. Histological and molecular analyses showed evidence of biological activity and that CAN-3110 injection was associated with immune activation and viral antigen persistence. Although definitive clinical efficacy cannot be determined in this small phase 1 study, OS of CAN-3110 treated subjects compares favorably to historical reports and warrants further clinical studies. Clinical trial information: NCT03152318.

scholarly journals EGFR-targeted intraoperative fluorescence imaging detects high-grade glioma with panitumumab-IRDye800 in a phase 1 clinical trial

Theranostics ◽  
2021 ◽  
Vol 11 (15) ◽  
pp. 7130-7143
Author(s):  
Quan Zhou ◽  
Nynke S. van den Berg ◽  
Eben L. Rosenthal ◽  
Michael Iv ◽  
Michael Zhang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Fluorescence Imaging ◽  
Phase 1 ◽  
High Grade Glioma ◽  
High Grade ◽  
Phase 1 Clinical Trial ◽  
Intraoperative Fluorescence Imaging ◽  
Intraoperative Fluorescence

scholarly journals ATIM-04. PHASE I IMMUNOVIROTHERAPY TRIAL OF IL-12 EXPRESSING HSV-1 (M032) IN PET DOGS WITH SPONTANEOUS HIGH GRADE GLIOMAS: A PRELIMINARY REPORT

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi2-vi2
Author(s):  
M Renee Chambers ◽  
David Crossman ◽  
Jeremy Foote ◽  
Jey Koehler ◽  
James Markert ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Brain Tumors ◽  
Phase I ◽  
Tumor Antigens ◽  
Phase 1 ◽  
Malignant Gliomas ◽  
High Grade ◽  
Pet Dogs ◽  
High Grade Gliomas ◽  
Hsv 1

Abstract Malignant gliomas are the most common primary brain tumors in humans, accounting for approximately 30% of all primary central nervous system (CNS) tumors in adults. Incidence and outcomes of gliomas in pet dogs are similar to humans. Previous methods of studying gliomas in rodent models do not adequately represent several features that define human cancers, most notably the sporadic nature of tumor development. Murine models lack intra-tumoral heterogeneity or hosts do not have an intact immune system. To overcome these rodent model deficiencies, many investigators have used canine models to study human diseases. We describe a prospective, phase I clinical trial in canine patients with sporadic high-grade gliomas to evaluate M032, a mutant HSV-1 expressing IL-12, alone or combined with a checkpoint inhibitor (Indoximod) to assess safety, tolerability and efficacy. M032 has been shown to infect and kill glioma cells, producing a virus and tumor cell antigen-rich debris field; will provide an increased adjuvant effect from released viral DNA recognized by TLR-9 receptors; and express IL-12 locally, stimulating activation of TH1 lymphocytes. The intratumoral inflammatory cell infiltration is expected to result in immune-related anti-viral responses with cross-epitope spreading to tumor antigens. Indoximod immunomodulation will be tested in latter cohorts to prolong anti-tumor responses. To date, six canines with high-grade gliomas have received intratumoral M032 without virus-related toxicities. Resected tumor and serial blood samples are being cryopreserved for analysis of lymphoid and monocyte/myeloid subset markers. This same virus is being tested in a phase 1 clinical trial in humans with high-grade malignant gliomas; eight human patients have received treatment at this writing without virus-related toxicities. The concurrent prosecution of both trials allows unprecedented real time comparison of safety and efficacy of immunovirotherapy as a stringent test of suitability of the dog as a valid and informative model of human brain tumors.

scholarly journals ATIM-26. IMMUNOLOGIC TRENDS ASSOCIATED WITH PATIENT OUTCOMES IN A PHASE 1 CLINICAL TRIAL OF TOCA 511 AND TOCA FC IN RECURRENT HIGH GRADE GLIOMA

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi6-vi7
Author(s):  
William Accomando ◽  
Timothy Cloughesy ◽  
Steven Kalkanis ◽  
Tom Mikkelsen ◽  
Joseph Landolfi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Patient Outcomes ◽  
Phase 1 ◽  
High Grade Glioma ◽  
High Grade ◽  
Phase 1 Clinical Trial

scholarly journals AT-46 * VORINOSTAT AND BEVACIZUMAB FOR RECURRENT HIGH-GRADE GLIOMA: INTERIM ANALYSIS OF A PHASE II CLINICAL TRIAL

2014 ◽  
Vol 16 (suppl 5) ◽  
pp. v18-v18
Author(s):  
K. Peters ◽  
D. Reardon ◽  
D. Randazzo ◽  
S. Dutton ◽  
A. Edwards ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Interim Analysis ◽  
High Grade Glioma ◽  
Phase Ii Clinical Trial ◽  
High Grade

scholarly journals Dynamics of Circulating γδ T Cell Activity in an Immunocompetent Mouse Model of High-Grade Glioma

PLoS ONE ◽  
2015 ◽  
Vol 10 (5) ◽  
pp. e0122387 ◽  
Author(s):  
Benjamin H. Beck ◽  
Hyunggoon Kim ◽  
Rebecca O’Brien ◽  
Martin R. Jadus ◽  
G. Yancey Gillespie ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
Cell Activity ◽  
High Grade Glioma ◽  
High Grade ◽  
Γδ T Cell ◽  
Immunocompetent Mouse

scholarly journals ACTR-59. A PHASE 1 STUDY OF BPM31510 PLUS VITAMIN K IN SUBJECTS WITH HIGH-GRADE GLIOMA THAT HAS RECURRED ON A BEVACIZUMAB-CONTAINING REGIMEN

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi27-vi27
Author(s):  
Lawrence Recht ◽  
Reena Thomas ◽  
Sophie Bertrand ◽  
Priya Yerballa ◽  
Gordon Li ◽  
...  
Keyword(s):  
Phase I ◽  
Vitamin K ◽  
Phase I Study ◽  
Phase 1 ◽  
High Grade Glioma ◽  
High Grade ◽  
Open Label ◽  
Open Label Phase ◽  
Grade 3

Abstract BACKGROUND High-grade gliomas (HGG) are characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an ubidecarenone (coenzyme Q10) containing lipid nanodispersion, causes a switch in cancer energy sourcing from glycolysis towards mitochondrial oxidative phosphorylation in vitro, reversing the Warburg effect and suggesting potential as an anti-tumor agent. The current study is a phase I study of BPM31510 + vitamin K in GB with tumor growth after bevacizumab (BEV). METHODS This is an open-label phase I study of BPM31510 continuous infusion with weekly vitamin K (10mg IM) in HGG patients using an mTPI design, starting at 110mg/kg, allowing for a single dose de-escalation and 2 dose-escalations. Patients had received first-line ChemoRadiation and were in recurrence following a BEV containing regimen. RESULTS 9 eligible and evaluable patients completed the 28 day DLT period. 8 patients had primary GB, 1 had anaplastic astrocytoma with confirmed pathologic transformation to GB. Median age was 55 years (27–67) and median KPS 70 (60–90) at enrollment. 4 patients were treated at the highest dose 171mg/kg, where there was a single DLT: Grade 3 AST & ALT. The most common grade 1–2 AEs possibly, probably or definitely related to drug were elevated AST, rash, and fatigue, each occurring in 3 patients. Median OS for 9 eligible/evaluable patients was 128 days (95% CI: 48–209) while PFS was 34 days (CI of mean 8.9). 3 patients are currently alive; 2 patients have survived >1 year. PK/PD data are being processed and will be presented. CONCLUSION This study confirms that BPM 31510 + vitamin K is safe and feasible in treatment-refractory HGG patients. Though this study demonstrates safety at 171mg/kg, the proposed dose for future studies in GB, based on additional pre-clinical and non-GB clinical data is 88mg/kg.

scholarly journals PDCT-06. PHASE 1 STUDY OF ONC201 IN PEDIATRIC PATIENTS WITH H3 K27M-MUTANT HIGH GRADE GLIOMA OR NEWLY DIAGNOSED DIPG

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi201-vi201
Author(s):  
Sharon Gardner ◽  
Fernando Suarez ◽  
James M Stafford ◽  
Rohinton S. Tarapore ◽  
Krystal Merdinger ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Phase 1 ◽  
High Grade Glioma ◽  
High Grade ◽  
Newly Diagnosed ◽  
Phase 1 Study

scholarly journals ATIM-05. COMPLEMENTARY CLINICAL AND ANCILLARY DATA FROM 123 PATIENTS WITH RECURRENT HIGH GRADE GLIOMA FROM THREE PHASE 1 TRIALS OF TOCA 511 AND TOCA FC: UPDATE AND JUSTIFICATION FOR A PHASE 2/3 TRIAL

2016 ◽  
Vol 18 (suppl_6) ◽  
pp. vi18-vi18 ◽  
Author(s):  
Manish Aghi ◽  
Michael Vogelbaum ◽  
Steven Kalkanis ◽  
Daniela Bota ◽  
Bob Carter ◽  
...  
Keyword(s):  
Phase 1 ◽  
High Grade Glioma ◽  
High Grade ◽  
Phase 2 ◽  
Ancillary Data ◽  
Phase 1 Trials ◽  
Three Phase

Safety of nivolumab in combination with dendritic cell vaccines in recurrent high-grade glioma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13526-e13526
Author(s):  
Katherine B. Peters ◽  
Gerald E. Archer ◽  
Pamela Norberg ◽  
Weihua Xie ◽  
Stevie Threatt ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Surgical Resection ◽  
Phase 1 ◽  
Randomized Study ◽  
High Grade Glioma ◽  
Checkpoint Blockade ◽  
Phase Iii ◽  
High Grade ◽  
Who Grade ◽  
Dc Vaccine

e13526 Background: Recurrence of high-grade glioma (HGG) (WHO grade III-IV) is a nearly universal phenomenon and necessitates the development of new therapeutic modalities. Two possible immunotherapeutic modalities are checkpoint blockade with agents such as nivolumab, a blocking antibody against the inhibitory checkpoint programmed cell death-1 (PD-1), and dendritic cell (DC) vaccination. We have shown in phase 1 and 2 trials that DC vaccination against the glioblastoma (GBM)-associated antigen human cytomegalovirus pp65-lysosomal-associated membrane protein (CMVpp65) is safe and possesses potential benefit. We hypothesized that nivolumab-induced immune checkpoint blockade could enhance efficacy of DC vaccination. Therefore, we undertook a phase 1 study to evaluate safety of nivolumab in combination with CMVpp65 mRNA pulsed DC vaccination in subjects with first or second recurrence of resectable HGG. Methods: We performed a phase 1, single-center, randomized study of nivolumab alone versus nivolumab + DC vaccination prior to planned surgical resection for both groups. We administered nivolumab 3 mg/kg IV q2weeks for 8 weeks followed by surgery and planned continuation of nivolumab. For the group receiving nivolumab + DC vaccination, we administered 3 vaccines before surgical resection with both groups receiving 5 planned post-resection DC vaccines. Primary endpoint was safety assessment using NCI-CTCAE 4.03. Results: We enrolled 6 subjects (4: GBM, 1: anaplastic astrocytoma, 1: anaplastic oligodendroglioma) with 3 receiving nivolumab alone and 3 receiving nivolumab + DC vaccination. Age range was 45-63 years subjects. We documented similar adverse events in both groups with most common grade 1-2 toxicities being fatigue (2 subjects, nivolumab alone) and thrombocytopenia (2 subjects, nivolumab + DC vaccine). Grade 4 toxicities included wound infection (2 subjects, nivolumab + DC vaccine) and meningitis (1 subject, nivolumab + DC vaccine). While we designed the study to enroll 66 subjects, we terminated the study early in light of CheckMate 143 phase III data showing nivolumab did not improve overall survival in recurrent GBM. Conclusions: Safety of nivolumab + DC vaccination in recurrent HGG is similar to nivolumab alone. Continued evaluation of new therapeutics including immunotherapy is underway for this patient population. Clinical trial information: NCT02529072.

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