The clinical trial demonstrates the safety of the targeted treatment approach for fatal brain cancer in children

The clinical trial demonstrates the safety of the targeted treatment approach for fatal brain cancer in children

A Phase I clinical trial showed that a targeted approach to treating a fatal brain tumor in children called diffuse intrinsic pontine glioma (DIPG) is safe, Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center researchers reported. This is the first larger study using a radiation-based direct drug approach to treatment and imaging.

DIPG is an aggressive cancer with no effective treatment – ​​celebrated as 10% of children survive two years after diagnosis. The tumor embeds itself in the brainstem, which regulates important functions including breathing, heart rate and muscle control. Neither chemotherapy drugs nor surgery can reach the difficult place at the base of the brain.

The new study, published Feb. 19 in Neuro-Oncology, found that infusing a drug called 124i-omburtamab directly into the brainstem maximizes delivery of the drug exactly where DIPG tumors develop—without the rest of the body.

We have shown that we can deliver the drug, and we can do it safely. Now we can lay the groundwork for changes, adjustments, retouches and planning. “

Dr.

Direct delivery

As the name suggests, DIPG tumors are not clearly contained in a separate mass, but rather diffuse through and infiltrate healthy tissue, making treatment difficult.

Dr. Souweidane and his team used a recently approved technique called convection enhanced delivery (CED) to inject a drug directly into the tumor region. IBD involves the use of a syringe attached to a long, thin tube inserted into a patient's brain. Gentle pressure on the syringe delivers medication through the tube to a targeted area of ​​the brain. Testing the technique in preclinical models showed that the brainstem could be accurately targeted and the volume of fluid injected into the brain could be tolerated without injury. “This has opened up an amazing opportunity and hopefully we could do that,” he said.

After testing many classes of therapeutic agents, the researchers chose 124i-burtamab, a radio monoclonal antibody that binds to a protein overexpressed in the tumor cells. The antibody finds the tumor cells and delivers a dose of radiation that kills them. At the same time, the drug can be visualized in positron emission tomography (PET) scan images, showing how much drug is delivered to the brain, how quickly it gets there, and how accurate it is. The body eventually clears out the radiation within a few weeks.

Ready for the next phase

In 2018, Dr. Souweidane conducted an initial study in Lancet Oncology with 28 children receiving IBD treatment for DIPG. This new study is a Phase I clinical trial of 50 patients to evaluate safety and determine the best drug dosages to treat DIPG. They used CED to slowly infuse 124-burtamab into patients' brains over 12 hours and performed PET scans before and after infusions.

“We reproducibly demonstrated that our approach increased the therapeutic concentration at the tumor site by nearly 1,000 times greater than in the whole body,” said Dr. Souweidane, who is also director of pediatric neurological surgery. “We essentially eliminate the concern about systemic toxicity, which typically limits the dose we can administer.”

The team found that the maximum tolerated activity of the drug was 6 millicuries. They also found that patients could safely tolerate up to 8 milliliters, just over a teaspoon, of the drug. There were no clinically significant procedure-related complications or deaths. However, the researchers note that the infusion site and the patient's preoperative symptoms likely play a significant role in drug tolerance.

"For someone like me, who has been in this field for about 40 years, 'survival' is not a word we use with this disease - these results offer a glimmer of hope where there was none," said Dr. Souweidane. "There are three long-term survivors. One is approaching four years, one is about seven years and another is almost 11 years past diagnoses." Although this study did not evaluate effectiveness, about 18% of patients lived for two years after diagnosis.

The next step is a Phase I/II clinical trial to test a new form of the drug and methodically evaluate how effective this treatment is for a larger group of DIPG patients. “I'm excited and we're jumping in our heads,” said Dr. Souweidane.

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