A phase I clinical trial led by researchers at Cincinnati Children’s reports that the gamma secretase inhibitor MK-0752 was “well-tolerated” in children with refractory or recurrent central nervous system (CNS) malignancies.

The clinical trial was led by Maryam Fouladi, MD, MSc, medical director of neuro-oncology at the Cancer and Blood Diseases Institute. Results were published online Aug. 8 in the Journal of Clinical Oncology.

MK-0752 is a synthetic small molecule that inhibits the Notch signaling pathway, which may result in apoptosis in tumor cells. The drug is being developed by Merck & Co. as a potential treatment for breast cancer and other malignancies.

This trial, which involved 23 children, was intended to identify a maximum tolerated dose in pediatric patients. Malignancies among the participants included ependymoma, brainstem glioma, medulloblastoma/primitive neuroectodermal tumor, glioblastoma multiforme, atypical teratoid/rhabdoid tumor, malignant glioma, and choroid plexus carcinoma.

Patients received the drug once a day for three days every seven days, for a 28-day course. The first three children started at 200 mg/m2. There was no dose-limiting toxicity at the initial dose level, but two of six patients developed dose-limiting grade 3 liver toxicity at 260 mg/m2. There was no grade 4 toxicity, and no evidence of the diarrhea or gastrointestinal symptoms that have been seen in adults.

The researchers recommend further testing with a phase II clinical trial using a dose of 260 mg/m2 once daily, following a three-day-on, four-day-off dosing schedule.