A Phase I Trial of the ADAM-10 inhibitor, INCB007839, in Children with Recurrent/Progressive High-Grade Gliomas: A Report from the Pediatric Brain Tumor Consortium (PBTC-056)

Background Pediatric high-grade gliomas (pHGGs), including diffuse midline glioma (DMG) and diffuse intrinsic pontine glioma (DIPG), are the leading cause of central nervous system tumor-related morbidity and mortality in children. Neuronal activity promotes pHGG growth; one key mechanism is neuronal activity-regulated shedding of neuroligin-3 into the glioma microenvironment, mediated by protease ADAM (A Disintegrin and Metalloprotease) 10. INCB007839, an ADAM 10 inhibitor, was used in this trial to block neuroligin-3 shedding and thus strategically target the tumor microenvironment that promotes glioma progression. Study objectives were to determine safety, tolerability and recommended phase 2 dose. Methods Patients aged 3-21 years old with recurrent/progressive pHGGs, including DMG and DIPG, were eligible. One dose level (120mg/m2/dose twice daily [BID]) was tested, and the trial was amended to require prophylactic anticoagulation with enoxaparin due to a thrombotic toxicity. Results Twelve of 13 subjects were eligible, and 10 were evaluable for dose-confirming. Median age was 14.5 years (4.9-20.7 years). Diagnoses included: DIPG (n = 7, 58.3%), glioblastoma multiforme (n = 4, 33.3%), and anaplastic astrocytoma (n = 1, 8.3%). All patients were treated at DL1 and remained on study for 1-4 courses. The most common toxicities were lymphopenia, transaminitis, and fatigue. Nine patients progressed/relapsed during active treatment, 1 died on treatment, and 2 withdrew (1 prior to therapy). Conclusions INCB007839 was tolerated in the majority of patients at 120mg/m2/dose BID with concurrent prophylactic anti-coagulation, although MTD was not declared. These data, combined with foundational preclinical studies targeting neuron-cancer interactions, open the door to possible cancer neuroscience strategies for pediatric high-grade gliomas.