Delivery Device Sends 'Chemosurgery' to Brainstem Tumor

Kristin Jenkins

June 29, 2018

The first clinical trial to demonstrate the feasibility of a convection-enhanced delivery (CED) system that acts as "chemosurgery" in the brainstem could revolutionize treatment for one of the deadliest central nervous system tumors of childhood, according to researchers.

The study, led by Mark M. Souweidane, MD, director of pediatric neurological surgery at the Weill Cornell Brain and Spine Center at Weill Cornell Medicine and NewYork-Presbyterian Hospital in New York City, was published online June 15 in Lancet Oncology. Souweidane is also in the Department of Pediiatric Neurosurgery at Memorial Sloan Kettering Cancer Center, also in New York City.

Results from the dose-escalation phase 1 clinical trial in 28 pediatric patients with diffuse intrinsic pontine glioma (DIPG) show that a single infusion volume of about 4000 μL of the radiolabeled antibody 8H3 achieved a distribution volume similar to the average estimates of tumor volume.

Positron emission tomography–based dosimetry of the radiolabeled antibody — which was coupled to the radioisotope iodine 124 ([124I]-8H9) and targeted to the glioma-cell specific surface antigen B7-H3 — indicated that intralesional concentrations were a thousand-fold higher than elsewhere in the body. These high local levels were retained for more than 8 days, the researchers say.

These findings provide validation that CED "is highly efficient in delivering drugs into the target area with negligible systemic exposure," the study authors write. "This therapeutic strategy warrants further development for children with diffuse intrinsic pontine glioma." 

The findings may also "serve as a foundation on which to design studies of convection-enhanced delivery-based therapies in the brainstem," they add.

No dose-limiting toxicities were observed, indicating that the maximum tolerated dose had not been reached. The trial was not powered to assess overall survival, but the median overall survival of 25 evaluable patients was 15.3 months.

"This trial shows we can use this very powerful drug-delivery platform repeatedly and safely," Souweidane said in a statement issued by Weill Cornell Medicine.

CED has been tested in other brain cancers, including adult glioblastoma, but no other systematic clinical trials have looked at the use of CED in the brainstem, he said in an interview.

"I've committed my career to this," Souweidane told Medscape Medical News.

"We were challenged to safely get agents into parenchymal tissues and to eliminate off-target effects. Now that we have [evidence for] good dosimetry and safety in one of the most difficult targets in the brain, there's a dire need to move this forward. I am confident we are going to maximize clinical benefit."

Souweidane, who is co-director of the Children's Brain Tumor Project, described DIPG as "a horrible disease."

The tumor originates in the pons region of the brainstem, so neurologic resection is not an option. With palliative radiation and concurrent chemotherapy, the median overall survival is less than 12 months.

DIPG affects mostly children."You just watch these kids die with no alternative," said Souweidane. "It's constant, constant turmoil and tragedy."

In an accompanying editorial, Dannis G. van Vuurden, MD, PhD, from the Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands, agreed that CED appears particularly suited to treatment of DIPG in its early stages, when the tumor is small and restricted to a tiny compartment. However, he also pointed out that whether this improved local control will prevent metastases to the cerebellum, medulla oblongata, and thalamus remains to be seen.

"It is therefore appropriate to question whether convection-enhanced delivery will be able to reach all tumour-infiltrated areas in patients with advance disease or progression," said van Vuurden.

CED acts as local "chemosurgery" as cytotoxic drugs, small molecules, and monoclonal antibodies are slowly infused into the tumor and brain parenchyma under a continuous pressure gradient, said van Vuurden. However, metastases are detected in 3% of patients with DIPG at diagnosis and in 12.7% at relapse. Spread of DIPG beyond the pons is associated with locked-in syndrome, in which patients lose voluntary muscle control and are forced to communicate through eye movements alone.

"This is often the state in which patients with diffuse intrinsic pontine glioma ultimately die," van Vuurden said. "Conversely, if local disease control leads to improved overall survival, this might result in larger numbers of patients showing metastatic disease at progression or relapse, which might ultimately require convection-enhanced delivery to be part of a multimodal treatment strategy, in combination with additional therapeutic avenues that have yet to be explored."

Study Details

The trial, which began in May 2012, took place at Memorial Sloan Kettering Cancer Center in New York City. From April 5, 2012, to October 8, 2016, 28 patients age 3 to 21 years were enrolled 4 to 14 weeks after completing external-beam radiation therapy (54.0 to 59.4 Gy at 1.8 Gy per fraction for 30 to 33 fractions). Three patients could not be evaluated but were included in an assessment of procedure-related adverse events.

By scheduling the intervention and the 30-day observation period that followed when disease burden was at its lowest, tolerance and tumor coverage would be improved, the researchers predicted. They also thought this strategy would reduce any ambiguity between adverse events related to treatment and disease progression.

CED was used to deliver [124I]-8H9 in seven dose-escalation cohorts.

Patients received a single infusion of 9.25, 18.5, 27.75, 37, 92.5, 120.25, or 148 MBq, respectively, at a concentration of approximately 37 MBq/mL, for a period of up to 12 hours.

The agent — developed by Nai-Kong Cheung, MD, PhD, director of the Nai-Kong Cheung Lab at Memorial Sloan Kettering Cancer Center — has already proven effective in treating metastatic neuroblastoma to the brain, according to the Weill-Cornell statement.

The mean lesion absorbed dose was 0.39 Gy/MBq 124I, and systemic exposure was negligible. The average lesion–to–whole body ratio of radiation absorbed dose was higher than 1200, the study authors say.

Of the 28 patients, 1 (4%) had treatment-related transient grade 3 hemiparesis. Most motor weakness symptoms resolved spontaneously or with dexamethasone in the first 4 days after infusion. One patient (4%) had grade 3 skin infection, but  no treatment-related grade 4 adverse events or deaths occurred.

As of the interim analysis cutoff date on March 16, 2018, 25 patients had died because of disease progression. For the 3 surviving patients, median follow-up was 36.1 months.

"Patients exiting our trial often received subsequent treatments before progression occurred," the researchers note. "Nevertheless, the current results encouraged us to continue enrolling an expanded phase 1 cohort and to integrate this information into the design of a phase 2 trial, aiming to optimize drug distribution, tumor coverage, dosimetry, and scheduling."

This study was funded by the National Institutes of Health, the Dana Foundation, The Cure Starts Now, Solving Kids' Cancer, the Lyla Nsouli Foundation, Cookies for Kids' Cancer, the Cristian Rivera Foundation, Battle for a Cure, the Cole Foundation, Meryl & Charles Witmer Charitable Foundation, Tuesdays with Mitch Charitable Foundation, and Memorial Sloan Kettering Cancer Center (MSKCC). The antibody 8H9 was licensed by MSKCC to Y-mAbs Therapeutics. Souweidane disclosed a relationship with Aesculap. Inventor and study coauthor Cheung disclosed financial relationships with Y-mAbs Therapeutics, Abpro-Labs, Eureka Therapeutics, and Biotec Pharmacon. Several other study authors disclosed competing financial interests. van Vuurden has disclosed no relevant finanacial relationships.

Lancet Oncol. Published online June 15, 2018. Abstract, Editorial

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