P08.32 TG02, an oral CDK inhibitor, demonstrates activity in glioma models: EORTC Brain Tumor Group Conducts Phase 1b study (STEAM / EORTC 1608)

Abstract

Introduction TG02 is an orally-bioavailable, multi-kinase inhibitor. Its primary anti-tumor mechanism of action is through CDK9-dependent depletion (IC50 = 3nM) of oncoproteins such as Mcl-1 and MYC. TG02 also strongly inhibits CDK5 (IC50 = 4nM). MYC, Mcl-1 and CDK5 are frequently overexpressed in glioblastoma (up to 80%); concurrently or separately. In an in vitro panel of patient-derived glioma cell lines, TG02 demonstrated significant anti-tumor activity (IC50 range = 25–150 nM). At equimolar concentrations, TG02 was thus 200–2500 times more potent than temozolomide in the same panel. Clinical pharmacokinetics from a recently completed Phase 1b study in multiple myeloma demonstrate that TG02 exposures in humans are sufficient for achieving inhibitory concentrations required in the majority of the glioma cell lines tested. Preclinical studies in mice have demonstrated that TG02 is a good candidate for development in gliomas since TG02 is not a substrate of P-GP (in vitro) and concentrations in the brain are 2.4 times higher than in plasma.Clinical Plan Based on the strong preclinical data for TG02, the EORTC Brain Tumor Group is currently conducting the STEAM 1608 study, a phase 1b dose-escalation and safety study of TG02 in combination with either hypofractionated radiotherapy or temozolomide in elderly patients with glioblastoma. Patient allocation to treatment will be determined by MGMT promoter methylation status according to EANO guidelines for elderly patients with glioblastoma or anaplastic astrocytoma. We will report on the current preclinical stage of development of TG02 and update on the clinical trial to be conducted by the EORTC Brain Tumor Group.