CTP-05. VAL-083 for treatment of Histone H3-Wild Type Diffuse Midline Glioma

Abstract Diffuse midline gliomas (DMG), are rare but aggressive CNS tumors primarily affecting children, and younger adults. H3K27M mutation is associated with worse prognosis and O6-Methylguaninemethyl transferase (MGMT) is usually unmethylated, predicting a poor response to temozolomide in these patients. As surgical intervention is not normally possible, standard of care treatment for DMG includes radiotherapy followed by chemotherapy. ONC201 is a selective dopamine receptor D2 (DRD2) antagonist showing preferential activity in H3K27M-mutant DMG, and has demonstrated significant survival benefit in patients with this mutation. However, DMG lacking the H3K27M mutation represents a heterogeneous group with variable biology and limited treatment options. These tumors frequently exhibit MGMT promoter unmethylation, contributing to resistance to treatment with alkylating agents such as temozolomide. For patients without a H3K27M mutation, radiation therapy remains the primary standard of care offering temporary symptom control but little survival benefit. The prognosis remains poor, with median survival under 12 months, underscoring the urgency for novel treatments for this DMG sub-group. VAL-083, a bi-functional DNA cross-linking agent active independent of MGMT status, is being evaluated in clinical trials for these molecular subtypes. Its mechanism of action bypasses MGMT-mediated DNA repair, providing effectiveness in MGMT-unmethylated tumors. VAL-083 crosses the blood brain barrier and has demonstrated activity against various DMG cell lines, and increased survival of animals in DIPG xenograft models compared to controls. VAL-083 has demonstrated increased survival of patients with GBM (MGMT unmethylated promoter) in newly diagnosed disease when co-administered with radiotherapy, or as adjuvant therapy, compared to historical standard of care. A phase 2 study will be conducted with VAL-083 in patients (12 years and older) with DMG without a H3K27M mutation. VAL-083 will be co-administered with radiotherapy, and up to 12 cycles of treatment every 21 days. Further details on the study design will be presented at the conference.