A first-in-human phase I single-agent dose-escalation, food effect and dose expansion study of oral ONC206 in recurrent and rare primary central nervous system neoplasms.

TPS2576Background: Blockade of the dopamine receptor D2 (DRD2) has emerged as a therapeutic target in neuro-oncology. ONC201, a first-generation imipridone that antagonizes DRD2, has demonstrated clinical activity in Diffuse Midline Gliomas, H3K27M-mutant (DMGs). Treatment options beyond surgical resection and radiation therapy are limited for most recurrent and rare primary CNS neoplasms. DRD2 blockade holds promise as a therapeutic target in multiple primary CNS cancers. ONC206 is a next generation imipridone and a chemical analog of ONC201 that possesses favorable drug properties such as oral bioavailability, robust stability, and blood-brain barrier penetrance. ONC206 exhibits enhanced allosteric inhibition of DRD2 and nanomolar affinity/potency as a DRD2 antagonist with complete antagonism and specificity for DRD2. ONC206 demonstrated broad spectrum anti-cancer efficacy in vitro across most solid tumor types tested in a panel of > 1000 human cancer cell lines with nervous system tumors emerging as most responsive. In addition to its broad-spectrum activity in vitro, ONC206 efficacy has been demonstrated in xenograft mouse models. Methods: This is an open label, dose escalation, and food effect Phase I study of ONC206at the National Cancer Institute, Neuro-Oncology Branch. Adult patients 18 years and older with recurrent, primary CNS neoplasms will initially be accrued to the dose escalation portion of the study and evaluated for toxicity. Eligible diseases include recurrent glioblastoma, WHO Grade 2 and 3 infiltrating glial neoplasms, and rare primary CNS neoplasms in the NCI-CONNECT program: DMGs, ependymomas, medulloblastomas, and other rare CNS tumor types. The primary endpoint is to determine DLT during the first cycle (28 days). Dose escalation will proceed according to a standard 3+3 design. Both once weekly and more frequent dosing of ONC206 will be explored in the dose escalation scheme. After the MTD is established, food effect will be determined in a dedicated cohort using a balanced, single-dose, two-arm, two-period crossover design. Secondary endpoints will include objective response rate by RANO criteria, overall and progression-free survival, and disease control rate. Exploratory analysis of DRD2 and DRD5 expression, DRD2 dimerization, expression of MYC and N-MYC in tumor tissue in relation to clinical outcomes will also be performed.