Abstract CT252: A dose escalation phase I study of concurrent GDC-0084 with radiation therapy for patients with solid tumor brain metastases or leptomeningeal metastases harboring PI3K pathway mutations
Authors: T. Jonathan Yang, Zhigang Zhang, Robert Young, James S. Garner, Jeremy Simpson, Adrienne Boire, Michael Offin, Eli Diamond
Journal: Cancer Research (2020)

Abstract Patients with metastatic solid tumors frequently develop central nervous system (CNS) metastases as part of their disease course. Radiation therapy (RT) is an effective treatment for disease control and symptom management of CNS metastases. Genomic predictors of poor CNS disease control include patients whose tumors harbor PI3K pathway alterations. Hyperactivation of the phosphatidylinositol-3-kinase/protein kinase b (PI3K-Akt) pathway has been associated with radioresistance. GDC-0084 (paxalisib) is a potent, oral, selective, CNS-penetrant small molecule inhibitor of phosphoinositide 3-kinase and of mammalian target of rapamycin (PI3K/mTOR) that has been specifically designed for treatment of CNS tumors. It is active against all four isoforms of PI3K (α, β, γ, and δ) and has moderate activity against mTOR. While PI3K inhibitors usually elicit cytostatic activity, they are thought to enhance radiation-induced DNA damage, G2/M arrest and apoptosis when combined with radiation. The synergistic effect is due to the abrogation of RT-induced phosphorylation of Akt with PI3K-Akt inhibition and therefore downregulation of the prosurvival pathways. In addition, PI3K inhibitors have been found to cause significant decrease in glycolysis at the step catalyzed by aldolase, and the inhibition of aldolase leads to the reduction of its product, Ga3P, which is the source for nucleotide synthesis. This has significant implication in a cell's ability to undergo efficient DNA repair and causes DNA damage through nucleoside depletion. This is a single institution, open label, prospective phase I clinical trial for patients with metastatic solid tumors harboring PI3K pathway mutations with parenchymal brain metastases or leptomeningeal metastases. Our primary aim is to assess the toxicity and safety of concurrent GDC-0084 administration with RT (30Gy in 10 fractions) to the brain (NCT04192981). Efficacy (local control per Response Assessment in Neuro-Oncology, intracranial progression-free survival, overall survival) will be evaluated as a secondary objectives. Pre- and post-treatment cerebrospinal fluid (CSF) biomarkers including circulating tumor cells, mutated allelic burden in cell-free DNA, cytokines, RNA and protein analysis of the cellular component will also be investigated as exploratory objectives. The starting dose of GDC-0084 is 45mg daily and a maximum of 24 patients will be required to establish the maximum-tolerated dose (MTD). Once the MTD is determined, an expansion cohort of 12 patients will be treated. Citation Format: T. Jonathan Yang, Zhigang Zhang, Robert Young, James S. Garner, Jeremy Simpson, Adrienne Boire, Michael Offin, Eli Diamond. A dose escalation phase I study of concurrent GDC-0084 with radiation therapy for patients with solid tumor brain metastases or leptomeningeal metastases harboring PI3K pathway mutations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT252.