Background: ATM inhibition has been hypothesized to potentiate the effects of radiation by preventing acute phase DNA damage repair, and a Phase 1 trial of this combination in patients with GBM is ongoing (NCT03423628). To test this hypothesis, this Phase 0/1b study evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of AZD1390, a first-in-class ATM inhibitor, in combination with radiation in newly-diagnosed GBM patients (NCT05182905).

Methods: Presumed newly-diagnosed GBM patients received 3 days of AZD1390 prior to planned resection at 4-6 or 23-25 hours following the final dose. Tumor tissue, cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase. ATM inhibition was assessed via ex vivo tissue radiation, quantifying pRAD50 levels compared to non-radiated control. Patients exceeding the PK threshold (2 nM unbound drug levels in Gd-non-enhancing tumor region) with unmethylated MGMT promoter were eligible for the expansion phase of study drug, combining AZD1390 with 6 weeks of radiotherapy.

Results: Seventeen patients were enrolled into the study. All tested patients (n=14) exceeded the PK threshold and qualified for the expansion phase. Three patients were excluded from the PK analysis due to dosing deviation (n=1) and non-GBM diagnosis (n=2). The mean unbound concentration of AZD1390 in Gd-nonenhancing tumor was 12.4 and 4.4 pmol/g, respectively, for the 4-6 and 23-25-hours cohort. Following 5Gy ex vivo radiation of surgical specimen, pRAD50 expression was significantly suppressed in AZD1390 treated patients compared to untreated controls (median 0.2% for 4-6-hours cohorts and 1.9% for 23-25-hours cohort vs 32.3% for control cohort, average 99% and 95% reduction, respectively, p<0.01 for both cohorts vs control). As of 11/30/2023, 3 patients with unmethylated MGMT promoter are undergoing therapeutic dosing of AZD1390 plus radiotherapy, with median clinical follow-up of 2.3 months.

Conclusion: AZD1390 is well-tolerated in newly-diagnosed GBM patients, achieving pharmacologically relevant concentrations in Gd-nonenhancing tumor tissue, and substantially suppressing radiation-induced increases in pRAD50 levels. These data are the first in GBM patients demonstrating AZD1390-mediated pharmacodynamic and pharmacokinetic response.

Citation Format: Nader Sanai, Siddhi Desai, Tigran Margaryan, Jennifer Molloy, Costanza LoCascio, Mackenna Elliott, Jocelyn Harmon, Amy Hong, Ernesto Luna Melendez, John Wanebo, Kelly Braun, William Kennedy, Michael Garcia, Wonsuk Yoo, Artak Tovmasyan, An-Chi Tien, Shwetal Mehta. A phase 0/1b study of AZD1390 plus radiotherapy in newly-diagnosed, MGMT-unmethylated glioblastoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT044.