Chemotherapy for high grade glioma (HGG) is limited by the poor activity of available agents and the compromised delivery of chemotherapy across the blood brain barrier. With these limitations in mind, the proposed phase I clinical trial utilizs two delivery modalities which may improve the efficacy of chemotherapeutic agents: liposomal irinotecan and MR imaged real-time convection enhanced delivery (CED). Several anticancer drugs have been encapsulated in liposomes, and have demonstrated therapeutic benefits over their unencapsulated counterparts. Thus, an appropriately designed liposome formulation of irinotecan may reduce the toxicity to healthy tissue while maintaining and increasing its anti-tumor potency. A major advance in the use of CED is the development of real-time MR imaged CED, which utilizes MRI to visualize the CED in real-time with the aid of co-convected contrast agents. CED improves chemotherapeutic delivery to brain tumors by utilizing bulk flow, or fluid convection, established as a result of a pressure gradient. Additionally, CED both obviates the challenges of crossing the BBB while minimizing systemic toxicity. The use of real-time MR imaging allows us to monitor CED into the brain and to take corrective action for technical complexities; this represents an important improvement over recent CED clinical trials which lacked effective imaging monitoring. Consequently, armed with our published preclinical work, with the support of an industry partner, and ultimately via this grant, we propose the first in human phase I study of CED of liposomal-irinotecan using real-time imaging with gadolinium in patients with recurrent HGG. We'll also examine the imaging data from this trial in an effort to optimize the MR image-guided intracranial injection procedure in HGG patients by correlating the observed distribution of gadolinium to pre-treatment modeling of the drug distribution utilizing predictive imaging software.

Public Health Relevance

Overall survival for patients with high grade glioma (HGG) is limited by the poor activity of available agents and the compromised delivery of chemotherapy across the blood brain barrier. The proposed phase I clinical trial aims to offset these difficultis with the novel use of liposomal irinotecan administered via real time convection enhanced delivery. If the proposed first in human study is proven to be tolerable and safe it would lead to an efficacy based study with the goal of improving survival for patients with HGG.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-SBIB-W (56))
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Zhang, Huiming
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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