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OBJECTIVES Convection-enhanced delivery (CED) provides pharmacokinetic advantages over systemic delivery for achieving cytotoxic drug levels into targeted regions of the brain. A major shortcoming of CED has been the need to limit treatment duration because of infection risks associated with external pumps. We engineered a subcutaneously implanted catheter-pump construct for prolonged CED which was successfully tested in a large animal model and then approved by the FDA for a Phase Ib clinical trial with topotecan in patients with refractory glioblastoma (IND 131889). METHODS Five patients with recurrent glioblastoma underwent surgical implantation of a subcutaneous pump and catheter that infused intracerebral topotecan over 30 days. Gadolinium was co-infused as a surrogate tracer and advanced non-invasive radiographic imaging was used to monitor drug distribution and pharmacological effects. Tissue from multiple radiographically-localized regions of each tumor and surrounding brain was procured pre-treatment at the time of catheter implantation and then post-treatment when tumors were surgically resected. Tissue was used for drug level measurements and advanced molecular, genomic and cellular analysis of treatment effects. RESULTS Treatments were successfully completed in all five patients without significant complications. The safety and tolerability of treatment was validated by quality-of-life measures and neurological assessments. Noninvasive imaging demonstrated large and stable drug distribution volumes. Comprehensive tissue analysis demonstrated effective targeting of mitotically active tumor cells while sparing neurons. CONCLUSIONS We engineered a subcutaneously implanted catheter-pump construct for chronic CED that was successfully tested in a Phase Ib clinical trial with topotecan in recurrent glioblastoma patients. Analysis of pre- and post-treatment tissue showed significant anti-tumor activity from topotecan that was not harmful to normal brain. Chronic CED combined with non-invasive real time drug distribution monitoring provides a safe and effective glioma strategy suitable for clinical use.

CTNI-25. PHASE IB CLINICAL TRIAL OF CHRONIC CONVECTION-ENHANCED DELIVERY OF TOPOTECAN FOR RECURRENT GLIOBLASTOMA