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

TPS4119 Background: Successful treatment of patients with colorectal peritoneal carcinomatosis highly depends on complete surgical tumor resection of all tumor. Oncological outcomes can potentially be improved by intraoperative imaging using a tumor-targeting antibody conjugated to a fluorophore and a radiotracer. This enables preoperative radionuclide imaging, real-time intraoperative fluorescence imaging and gamma detection. In this study we investigate the feasibility, accuracy and safety of CEA-targeted preoperative SPECT/CT and intraoperative fluorescence imaging in patients with colorectal PC. Methods: In this phase I/II single arm protein dose escalation study patients with peritoneal metastases of colorectal origin who are scheduled for cytoreductive surgery and HIPEC will receive an intravenous injection of the CEA-targeting tracer 111In-DOTA-labetuzumab-IRDye800CW. The first 15 patients will receive a single dose of 2,10 or 50 mg 6 to 7 days prior to surgery. Four to five days after injection SPECT/CT imaging of the thorax and abdomen is performed to determine intra-abdominal tumor load and detect extra-abdominal metatases. At day 6/7 after injection, standard cytoreductive surgical resection extended with real-time near-infrared fluorescence imaging and radio guidance is performed. After surgery, the peritoneal cavity will be re-examined for residual disease with fluorescence imaging. Resected specimens are analyzed microscopically, immunohistochemically (CEA and H&E) and by gamma counting. Blood samples are drawn for farmacokinetics and safety analysis at 180 minutes, 4 days, 6 days and 3 weeks after tracer injection. In the phase II dose expansion cohort, 14 more patients will receive the optimal dose as determined in the phase I trial. The primary objectives of the trial are to assess the safety, feasibility and accuracy of preoperative SPECT/CT and intraoperative fluorescence imaging after administration of 111In- labetuzumab-IRDye800CW in patients with peritoneal carcinomatosis of colorectal origin who will undergo cytoreductive surgery and HIPEC. The secondary objectives are to assess whether additional malignant lesions can be visualized by fluorescence imaging after cytoreductive surgery, to assess the intensity of fluorescence in malignant and non-malignant tissue, to assess the correlation between localization of the dual-labeled antibody and CEA expression in tumor and healthy tissue and to determine blood concentrations of the dual labelled antibody at several time points in patients. Clinical trial information: NCT03699332 .

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

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2009 ◽

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.

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