INCB7839 in Treating Children With Recurrent/Progressive High-Grade Gliomas

  • STATUS
    Recruiting
  • End date
    Dec 31, 2023
  • participants needed
    28
  • sponsor
    Pediatric Brain Tumor Consortium
Updated on 29 November 2020
Investigator
Shujie Han, Ph.D., CCRA
Primary Contact
Children's National Medical Center (5.3 mi away) Contact
+10 other location
corticosteroids
total body irradiation
filgrastim
monoclonal antibodies
biologic agent
nitrosoureas
measurable disease
sargramostim
anticonvulsants
antiretroviral agents
growth factor
MRI
erythropoietin
dexamethasone
seizures
epilepsy
metastasis
neutrophil count
blood transfusion
spinal cord
glioblastoma multiforme
astrocytoma
oligodendroglioma
anaplastic astrocytoma
tumor progression
anaplastic oligodendroglioma
astrocytoma, anaplastic
platelet transfusion
oligodendroglioma, anaplastic
biologics
dipg
diffuse intrinsic pontine glioma
spinal tumors
craniospinal irradiation

Summary

This is a multicenter phase 1 trial of INCB7839 for children with recurrent or progressive high-grade gliomas, including, but not limited to, diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs), after upfront therapy.

Description

INCB7839 is an inhibitor of the ADAM (A Disintegrin and Metalloprotease) 10 and 17 proteases. Neuronal activity regulates glioma growth through neuroligin-3 (NLGN3). ADAM 10 is the protease responsible for NLGN3 release into the tumor microenvironment and represents a promising therapeutic target.

Pre-clinical studies of INCB7839 in patient-derived pediatric high-grade gliomas (GBM and DIPG) revealed that INCB7839 inhibits pediatric high- grade glioma growth and improves overall survival. In vivo testing also demonstrated that INCB7839 penetrates brain tissue sufficient to achieve its pharmacodynamic effect of ADAM10 inhibition. Further pre-clinical studies in other animals revealed minimal toxicity, including non-adverse to mild increases in serum hepatobiliary enzymes, protein, calcium, cholesterol values, along with minimal decreases in RBC mass parameters; all parameters recovered.

INCB7839 has been evaluated in Phase I and Phase II clinical trials for previously treated solid tumors and breast cancer. Of the adverse events (AEs) noted, the majority were mild-to-moderate in severity, the most frequent being fatigue, nausea, anorexia, diarrhea, emesis, abdominal pain, anemia and constipation. The dose-limiting toxicity for monotherapy with INCB7839 in Phase I clinical trials was declared to be deep venous thrombosis (DVT). Out of 41 patients, there was a total of 9 thrombotic events including mild superficial thrombophlebitis (n=1), DVT (n=4), vena cava thrombosis with renal insufficiency in a patient with squamous cell cancer of the head and neck (n=1), atrial thrombosis in patient with breast cancer (n=1), and pulmonary embolism in patients with hormone-refractory prostate cancer (n=2). Overall, INCB7839 does exhibit a pro-coagulant effect in some adult patients, resulting in an increased incidence of DVT, whether used alone or in combination. The mechanism of this effect is unknown, and there is no clear relationship between the frequency of thrombosis and the dose administered.

Details
Treatment INCB7839
Clinical Study IdentifierNCT04295759
SponsorPediatric Brain Tumor Consortium
Last Modified on29 November 2020

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