New York University School of Medicine New York, NY
J. T. Yang1,2, P. Y. Wen3, B. S. Imber4, J. Drappatz5, R. Jena6, D. Forst7, A. Zukas8, S. C. Short9, C. Fan10, W. Trigg11, A. Milner11, U. Polanska12, C. Glover11, C. Stavraka11, D. Dalal10, D. Karanovic13, and A. Chalmers14; 1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 2New York University School of Medicine, New York, NY, 3Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, 4Memorial Sloan Kettering Cancer Center, New York, NY, 5University of Pittsburgh Medical Center, Pittsburgh, PA, 6University of Cambridge, Cambridge, United Kingdom, 7Massachusetts General Hospital, Boston, MA, 8Medical University of South Carolina, Charleston, SC, 9Leeds Institute of Medical Research at St. James’s, Leeds, United Kingdom, 10AstraZeneca, Gaithersburg, MD, 11AstraZeneca, Cambridge, United Kingdom, 12AstraZeneca, Warsaw, Poland, 13AstraZeneca, Waltham, MA, 14School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
Purpose/Objective(s): Glioblastoma (GBM), the most common primary brain malignancy in adults, is an aggressive cancer with limited life expectancy. The standard of care backbone for newly diagnosed GBM is intensity-modulated radiation therapy (IMRT) with concomitant and adjuvant temozolomide. AZD1390, an oral, highly potent, and selective ataxia telangiectasia mutated kinase inhibitor, is designed to augment the efficacy of IMRT without exacerbating neurotoxicity. AZD1390 is optimized for blood brain barrier penetration, confirmed in a human healthy volunteer PET study (NCT03215381) and a Phase 0 study in patients (pts) with GBM (NCT05182905). This global, Phase 1, open-label study (NCT03423628) evaluates the safety and preliminary efficacy of escalating doses of AZD1390 and radiation therapy (RT) in pts with GBM and brain metastases. Materials/
Methods: Eligible adult pts received escalating once-daily AZD1390 doses following a Bayesian continual reassessment method, with IMRT 35 Gy in 10 fractions over 2 weeks (Arm A, recurrent GBM) or IMRT 60 Gy in 30 fractions over 6 weeks (Arm C, newly diagnosed, O-6-methylguanine-DNA methyltransferase unmethylated GBM). Pts in both Arms received 2 additional weeks of adjuvant AZD1390 post-IMRT. Arm B included pts with brain metastases but was closed due to low recruitment and is not reported. Primary objective was safety; secondary objectives included clinical efficacy and pharmacokinetics (PK). Results: As of Feb 6, 2024, 115 pts have received AZD1390 (75 in Arm A; 40 in Arm C) at doses of 10–900 mg/day. PK was linear with a slightly more than dose-proportional increase and a mean terminal elimination half-life around 9–11 hours. Most patients had =1 treatment-emergent adverse event (AE); the most common were fatigue (51.3%), nausea (39.1%) and headache (38.3%). Grade =3 AZD1390-related AEs occurred in 18/115 pts (15.7%). The maximum tolerated dose was identified as 400 mg in Arm A and 300 mg in Arm C. Dose limiting toxicities included, but were not limited to, creatinine kinase elevation in Arm A and radiation skin injury in Arm C. Treatment was well tolerated, with the majority of reported AEs being low-grade. AEs led to discontinuation of AZD1390 in 13.0% of pts. The safety profile was consistent across Arms despite the different RT schedules; the most notable difference was in radiation skin injury, a reversible event, with higher frequency and severity in Arm C. At doses demonstrating target engagement in the Phase 0 study, median overall survival was 12.7 months (95% CI, 10.7, 18.9, n=21) for Arm A and is still maturing for Arm C. Conclusion: Concurrent AZD1390 and IMRT administration is tolerated with a manageable safety profile, at doses shown to achieve clear target engagement in the Phase 0 study. Preliminary efficacy is encouraging in Arm A. These data suggest the potential for AZD1390 to act as a radiosensitizer for the treatment of GBM. Clinical investigation is ongoing.
