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Two Novel Studies Seek to Improve Outcomes in Children with Malignant Fourth Ventricular Brain Tumors

The current outlook for children with recurrent malignant brain tumors originating from the posterior fossa is extremely poor. Most clinical trials offer systemic chemotherapy or re-irradiation, both of which can have a variety of side effects and frequently fail in children with recurrent tumors. Two new single-center trials under way at Children’s Memorial Hermann Hospital and McGovern Medical School at UTHealth are investigating novel therapies with the potential to improve outcomes for children with fourth ventricular brain tumors while avoiding systemic toxicity.

David SanbergConducted by David Sandberg, M.D., FAANS, FACS, FAAP, professor and director of pediatric neurosurgery at Children’s Memorial Hermann Hospital, the Memorial Hermann Mischer Neuroscience Institute at the Texas Medical Center, and UTHealth, the first trial, “A Combination Intraventricular Chemotherapy Pilot Study,” is investigating methotrexate and etoposide infusions into the fourth ventricle in children with recurrent posterior fossa brain tumors. The trial is open to patients age 1 to 21 with recurrent medulloblastoma, recurrent ependymoma and recurrent atypical teratoid/rhabdoid tumors involving the brain and/or spine.

“Despite advances in pediatric neurooncology, we’re still seeing too many children die of malignant brain tumors, and the treatments currently available are not satisfactory for children,” says Dr. Sandberg, who holds the Dr. Marnie Rose Professorship in Pediatric Neurosurgery at UTHealth. “Many suffer extreme toxicity from chemotherapy and radiation, and I believe we can do better. Novel approaches are needed to improve treatment outcomes.”

The primary objective of the new trial is to determine if combination intraventricular infusions of two agents, methotrexate and etoposide, are safe and can be infused without neurological toxicity. The secondary objective is to assess the antitumor activity of these infusions, in the hope that the infusions will yield even more robust treatment responses than those observed in the previous single-agent trials.

The second pilot study, “Infusion of 5-Azacytidine (5-AZA) into the Fourth Ventricle or Resection Cavity in Children with Recurrent Posterior Fossa Ependymoma,” is also open for enrollment to patients age 1 to 21.

“5-AZA is a DNA methylation inhibitor that has been infused in non-human primates with no neurological toxicity, while achieving substantial and sustained cerebrospinal fluid (CSF) levels,” Dr. Sandberg says. “Recent studies have demonstrated that DNA methylation inhibitors are logical therapeutic candidates for ependymomas originating in the posterior fossa. Our goals are to establish the safety of direct administration of 5-AZA into the fourth ventricle and also hopefully demonstrate the clinical efficacy of these infusions.”

Both clinical trials build on two previous recent trials conducted at Children’s Memorial Hermann Hospital and UTHealth, in which Dr. Sandberg demonstrated that repeated infusions of methotrexate into the fourth ventricle are well tolerated and do not cause new neurological deficits or other serious adverse events. “We have also demonstrated that some patients, all of whom had recurred despite surgery, radiation and chemotherapy, have a response to treatment with decreased tumor burden after the infusions,” he says.

Patients enrolled in the studies will undergo surgical placement of a ventricular catheter into the fourth ventricle or posterior fossa resection cavity with simultaneous surgical resection of recurrent tumor as indicated. Safety will be assessed through serial neurological examinations and MRI scans, and treatment response will be assessed via MRI scans of the brain and spine as well as lumbar punctures to assess CSF cytology.

Each of the two studies will enroll an estimated 10 patients. For questions about the studies or more information about enrollment, contact Marcia Kerr, RN, at marcia.l.kerr@uth.tmc.edu or by phone at (713) 500-7363 .