CTNI-42. PHASE I CLINICAL TRIAL OF PEPOSERTIB PLUS RADIATION IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GLIOBLASTOMA

Abstract

Abstract BACKGROUND DNA-dependent protein kinase (DNA-PK) is a pivotal component of DNA damage repair (DDR) pathways and is an attractive target in glioblastoma because its expression renders tumors less vulnerable to radiotherapy. Peposertib is a small molecule DNA-PK inhibitor that has been shown to potentiate radiotherapy and regress glioblastoma tumors pre-clinically. We conducted a two-stage phase I trial of peposertib plus radiation in newly-diagnosed MGMT-unmethylated glioblastoma (NCT04555577). Method: In stage 1, patients received peposertib plus standard-of-care radiotherapy to determine the maximum-tolerated dose (MTD) based on the Bayesian Optimal Interval design (maximum n = 24). Stage 2 is a window-of-opportunity expansion cohort and will include 5 surgical patients to evaluate tumor drug concentration. Both groups receive adjuvant temozolomide for 6-cycles. RESULTS Fifteen completed the 10-week dose-limiting toxicity (DLT) period; 3-50mg, 3-100mg, 3-200mg, 6-300mg. One DLT (G3 radiation necrosis [RN] at 300mg) was observed. Most notable toxicity was 3 patients with transient G3 dermatitis of the scalp (not DLT per protocol) (2-200mg, 1-300mg). Therefore, radiation dose constrains to the skin were incorporated and subsequent patients did not experience this toxicity. Next-generation sequencing (NGS) was available for 13 archival tissue. Two patients had pathology-proven RN (one within and one outside of the DLT period). Both tumors had mutations in DDR genes (i.e. ATRX, DICER1). Recurrent tissue was available for one patient after treatment with peposertib showed gain of two ATM mutations. CONCLUSION The initial safety data of peposertib plus radiation in newly-diagnosed MGMT unmethylated glioblastoma is favorable. The cases with RN in tumors with DDR mutations, the gain of two ATM mutations in a recurrent tumor and the cases of scalp dermatitis suggest that peposertib is active and possibly potentiates the effect of radiation. Safety and survival data and correlations with genomics will be presented. The study was supported by EMD Serono (CrossRef Funder ID: 10.13039/100004755).