Ctni-25. a phase 0/1b study of azd1390 plus radiotherapy in recurrent glioblastoma patients

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 aimed to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of AZD1390, an ATM inhibitor with BBB penetration, in combination with ex vivo radiation in patients with GBM (NCT05182905). METHODS Recurrent GBM patients received 3 days of AZD1390 prior to planned resection at 2-4, 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 radiation and quantification of pRAD50 levels compared to non-radiated control. Patients exceeding the PK threshold were eligible for an expansion phase of study drug plus radiotherapy followed by maintenance regimen. RESULTS In 17 patients treated to date, AZD1390 was consistently measured in the Gd-non-enhancing tumor region. All patients (n = 17) exceeded the PK threshold to qualify for the expansion phase of the study. With 5Gy ex-vivo radiation of surgical specimen, pRAD50 expression was significantly suppressed in AZD1390 treated patients compared to untreated controls (geomean 1.8% vs 29.1%, average 94% reduction, p < 0.01). Median 6-month progression-free survival has not been reached at a median clinical follow-up of 4.3 months. CONCLUSION AZD1390 is well-tolerated in recurrent GBM patients, achieving pharmacologically relevant concentrations in non-enhancing tumor tissue, and substantially suppressing induction of pRAD50 levels ex vivo post-radiation. This is the first pharmacodynamic evidence that AZD1390 may be a potent radio-potentiator in patients with GBM.