▎WuXiEdited by Kant Content Team

Recently, AstraZeneca announced positive results from the global Phase 1 trial of its investigational ATM kinase inhibitor AZD1390 at the American Association for Cancer Research (AACR) Annual Meeting. Analysis shows,When combined with standard radiotherapy, the treatment demonstrated manageable safety in patients with recurrent and newly diagnosed glioblastoma (GBM) and showed preliminary efficacy in patients with recurrent GBM.

This published study aims to evaluate the safety, tolerability, early efficacy, and maximum tolerated dose of AZD1390 in combination with radiotherapy (IMRT) in GBM patients. As of February 2024, 115 patients in this Phase 1 trial have received AZD1390 treatment, including 75 recurrent GBM patients in Group A and 36 newly diagnosed unmethylated patients in Group C.MGMTGBM patients with the gene promoter (uMGMT). In both groups, patients received escalating once-daily doses of AZD1390; Group A patients received IMRT treatment with 10 fractions of 35 Gy over two weeks; Group C patients received IMRT treatment with 30 fractions of 60 Gy over six weeks. Additionally, after completing IMRT treatment, patients received two weeks of adjuvant AZD1390 treatment.

The analysis shows,In achieving the goalDoseEncouraging results were observed in Group A patients.12.7 monthsMedian overall survival (OS). Previous studies have shown that the current standard treatment can achieve an OS of 6 to 10 months for patients.The OS data for Group C is not yet mature.

Among 115 patients, 18 (15.7%) experienced grade 3 or 4 AZD1390-related adverse events (AEs); no grade 5 treatment-related adverse events occurred. Additionally, 4.3% of patients discontinued AZD1390 treatment due to AZD1390-related adverse events.Most adverse reactions experienced by patients during the study were low-grade, easy to control, and reversible.Researchers determined that the maximum tolerated dose for Group A was 400 milligrams, and for Group C, it was 300 milligrams.

IMRT is the standard treatment for newly diagnosed GBM patients, which causes cancer cell death by damaging DNA within the cells. However, the ATM signaling pathway in cancer cells is often activated to help repair DNA double-strand breaks (DSB) caused by radiotherapy, thereby reducing the effectiveness of IMRT.AZD1390 is an ATM kinase inhibitor that prevents cancer cells from repairing DSB, thereby enhancing the anti-cancer effects of radiotherapy. A previous study in healthy volunteers showed that AZD1390 can cross the intact blood-brain barrier.Other preclinical experiments have also demonstrated the potential anti-tumor effects of AZD1390 without exacerbating the toxicity of IMRT to the surrounding normal healthy brain tissue.

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