Results of Phase 1 Trial of intra-arterial drug delivery for DIPG published in Journal of Neurosurgery: Pediatrics from Dr. Greenfield’s Lab.
Designing new routes of administration for targeted agents, antibodies or classic chemotherapies to inoperable brain tumors is central to the mission of the Children’s Brain Tumor Project. A major advance forward in these efforts was recently published from Dr. Greenfield’s group in the August issue of Journal of Neurosurgery: Pediatrics. The paper reports on the results of the first-in-kind clinical trial of an intra-arterial approach to chemotherapy drug delivery to the brain of children. The paper, “Intra-Arterial Delivery of Bevacizumab and Cetuximab Utilizing Blood Brain Barrier Disruption in Children with High Grade Glioma and Diffuse Intrinsic Pontine Glioma: Results of a Phase I Trial,” show intra-arterial delivery to be safe in pediatric patients. It also appeared to increase the average survival time for children with DIPG (children showed a mean survival rate of 17.3 months compared with less than one year, typical for this terminal disease). As a result, Weill Cornell Medicine has recently approved expansion into a multi-center trial, designating the University of Miami as a second site for enrollment.
Intra-arterial delivery is a precise surgical approach that delivers chemotherapy drugs by threading delicate microcathers to specific areas of the brain to increase drug concentration at the tumor site while reducing the potential for systemic side effects. This delivery method had not previously been tested in children with high-grade pediatric brain tumors including high-grade glioma and DIPG. Thirteen children were treated, and the method proved safe with no severe side effects. Central to this success was partnering with experienced Neuro-interventional surgeons, in this case Dr. Jared Knopman also at Weill Cornell, where the safety and efficacy of intra-arterial delivery for retinoblastoma was described by Dr. Pierre Gobin 20 years ago.
This new trial focused on delivering a combination of drugs, bevacizumab and cetuximab, through local arteries that directly feed a brain tumor rather than the retina. Prior to receiving the drugs to treat the tumor, patients on this trial were also given a dose of mannitol — a drug that opens the blood-brain barrier — to allow for the bevacizumab and cetuximab to better penetrate the tumor.
The next step is to conduct repeat monthly dosing to evaluate whether additional doses allow for better control of the disease. The trial is available for enrollment at Weill Cornell Medicine for repeat dosing and patients will soon be able to enroll at the University of Miami/Jackson Health System as well.
Working with Dr. Greenfield on this project was Dr. Heather McCrea, MD, a pediatric neurosurgeon at Nicklaus Children’s Hospital/University of Miami. Dr. McCrea, who completed her residency at New York-Presbyterian/Weill Cornell Medical Center in 2016, worked on this project for several years with Dr. Greenfield, Associate Professor of Pediatric Neurosurgery and co-founder of the Children’s Brain Tumor Project at Weill Cornell Medicine. Dr. McCrea trained under Dr. Greenfield and Dr. Mark Souweidane during her residency, then completed a fellowship in pediatric neurosurgery at Boston Children’s Hospital before accepting her current faculty position at the University of Miami.
“This trial was still in the concept phase when Dr. Greenfield and I first started working on the design,” said Dr. McCrea. “Even after I finished my residency we continued working together to move this trial forward, with the goal of expanding from a one-time dose to repeat dosing and adding additional sites including my current institution. Years of hard work went into this, so to see it come full circle like this is certainly rewarding.”
The exploration of alternative surgical approaches to drug delivery among pediatric brain tumor patients is foundational to the research underway at the Children’s Brain Tumor Project, Weill Cornell Medicine. Depending on the characteristics of the tumor, intra-arterial delivery is a promising approach to treating certain brain tumors, as are other approaches such as convection-enhanced delivery. These strategies allow for direct drug delivery to the tumor, effectively bypassing the blood brain barrier and reducing the systemic toxicity that is experienced with standard intravenous chemotherapy.