An interview with Jonathan T. Yang MD PhD, Washington University, Seattle, USA, (Formerly of Memorial Sloan Kettering Cancer Center, New York.)
SAN DIEGO, USA—An international phase one clinical study has found that a drug known to inhibit DNA damage repair was able to boost the efficacy of radiotherapy in patients being treated for their glioblastoma.
The radiosensitizer, AZD1390, an inhibitor of ataxia telangiectasia mutated (ATM) kinase, was tested as adjunctive therapy (combined with standard radiation plus temozolomide) among 115 patients who had recurrent or newly diagnosed glioblastoma.
First author Jonathan T. Yang MD PhD, of Memorial Sloan Kettering Cancer Center in New York, reported promising efficacy to the American Association for Cancer Research Annual Meeting in San Diego, where Audio Journal of Oncology correspondent Peter Goodwin caught up with him.
Audio Journal of Oncology: IN: [Sarah MAXWELL] “A radio sensitizer drug has shown …….OUT:…..from me, Sarah Maxwell, goodbye” 10:59secs
https://clinicaltrials.gov/study/NCT03423628
Abstract: “AZD1390 With Radiotherapy Shows Manageable Safety Profile and Preliminary Efficacy for Patients with Glioblastoma in Phase I Trial”
Journal ABSTRACT:
https://www.sciencedirect.com/science/article/pii/S0360301624009799
Safety and preliminary efficacy of AZD1390 + radiation therapy (RT) for glioblastoma.)
(IMRT) with 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 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.
Author Disclosure: J.T. Yang: Grant/research funding; AstraZeneca, Kazia Therapeutics, Debiopharm, Cantex Therapeutics. Compensation/Payment; Plus Therapeutics, Nanocan Therapeutics, Kazia Therapeutics. Stock options; Nanocan Therapeutics. P.Y. Wen: Independent Contractor; Anheart, AstraZeneca, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, GlaxoSmithKline, Kintara, Merck, Mundipharma, Novartis, Novocure, Prelude Therapeutics, Sagimet, Sapience, Servier, Symbio, Tango, Telix, VBI Vaccines. Grant/research funding; AstraZeneca, Black Diamond, Bristol Myers Squibb, Chimerix. B.S. Imber: Grant/research funding; AstraZeneca. Honoraria; GT Medical Technologies, Telix Pharmaceuticals. J. Drappatz: Grant/research funding; Novocure, Servier, Novartis. Copyright/Patent/License/Royalty; Elsevier, Wolters Kluwer. Stock; Pfizer, GlaxoSmithKline, Gilead. R. Jena: None. D. Forst: Grant/research funding; American Society of Clinical Oncology. Stock; Eli Lilly. A. Zukas: None. S.C. Short: None. C. Fan: Stock; AstraZeneca. W. Trigg: Stock; AstraZeneca. A. Milner: None. U. Polanska: Stock; AstraZeneca. C. Glover: Stock; AstraZeneca. Stock options; AstraZeneca. C. Stavraka: Stock; AstraZeneca. D. Dalal: Stock; AstraZeneca. D. Karanovic: None. A. Chalmers: Grant/research funding; AstraZeneca. Honoraria; AstraZeneca.
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PRESS RELEASE:
AZD1390 With Radiotherapy Shows Manageable Safety Profile and Preliminary Efficacy for Patients with Glioblastoma in Phase I Trial
SAN DIEGO – AZD1390, an ataxia telangiectasia mutant (ATM) kinase inhibitor, demonstrated a manageable safety profile in both recurrent and newly diagnosed glioblastoma (GBM) patients when given in combination with standard-of-care radiotherapy and showed preliminary efficacy in recurrent GBM patients, according to results from a global phase I trial presented at the American Association for Cancer Research (AACR) Annual Meeting 2024, held April 5-10.
“Glioblastoma is a lethal cancer with the majority of patients not surviving past two years from diagnosis,” said Jonathan T. Yang, MD, PhD of Memorial Sloan Kettering Cancer Center, who presented the results of the trial. “Despite efforts to improve survival, the current standard of care continues to be a backbone of radiotherapy with or without temozolomide [Temodar] without much innovation in the past two decades. This context highlights both the urgent need to develop new medicines and the historical challenges of developing novel therapeutics for this devastating disease.”
Intensity-modulated radiation therapy (IMRT), which is the standard of care in newly diagnosed GBM patients, causes the death of cancer cells by damaging the DNA inside of the cell. But the ATM cell signaling pathway is activated to help repair the DNA double-strand breaks (DSBs) caused by radiation therapy, thus impeding its effectiveness. An ATM inhibitor prevents the repair of DSBs, thereby enhancing the cancer-killing effect of radiation therapy, Yang said.
GBM accounts for approximately 50% of primary malignant brain tumors. One reason brain tumors have been difficult to treat is because the blood-brain barrier prevents some therapies from penetrating into the brain and reaching the cancers they aim to treat. Because of this challenge, AZD1390 was designed to penetrate the blood-brain barrier and a healthy volunteer study recently showed that AZD1390 crossed through an intact barrier. Other pre-clinical experiments demonstrated the potential antitumor effects of AZD1390 without exacerbating IMRT toxicity in surrounding areas by not causing harm to normal, healthy brain tissue.
Yang and his colleagues assessed the safety, tolerability, early efficacy, and maximum tolerated dose of AZD1390 with IMRT in humans. As of February 2024, 115 patients were given AZD1390 in the phase I trial, including 75 patients with recurrent GBM in Arm A and 36 patients with newly diagnosed, MGMT unmethylated GBM in Arm C. In both Arms, patients received escalating once-daily doses of AZD1390; patients in Arm A were given 35 Gy of IMRT in 10 fractions over two weeks while those in Arm C were given 60 Gy of IMRT in 30 fractions over six weeks. Additionally, following the completion of IMRT, patients were given adjuvant AZD1390 for two weeks.
Out of the 115 patients, 18 (15.7%) experienced an AZD1390-related adverse event (AE) of a grade 3 or 4; there were no grade 5 treatment-related AEs. Additionally, 4.3% of patients discontinued AZD1390 treatment due to an AE related to AZD1390 only.
“Most adverse effects experienced by patients during the study were low grade, readily manageable, and reversible in nature,” Yang said.
AZD1390 With Radiotherapy Shows Manageable Safety Profile and Preliminary Efficacy for Patients with Glioblastoma in Phase I Trial
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Patients in Arm C experienced a higher frequency and severity of radiation-related skin injury due to longer exposure to radiation, and most instances were easily managed and fully reversed following treatment with topical steroids and moisturizers, Yang said.
The researchers identified 400 mg in Arm A and 300 mg in Arm C as the maximum tolerated doses. While Yang said they are still collecting efficacy data in both arms,
. Prior studies have shown the current standard of care leads to an OS of 6 to 10 months. The OS data for
Arm C is still maturing.
“Drug development in GBM is generally challenging due to the rarity of the disease and lack of robust early clinical indicators of efficacy,” Yang said. “If the preliminary efficacy benefit observed in this trial is proven in a pivotal study, it would be a critical, biologically supported approach to address the high unmet need in GBM.”
Yang said the planning for the next phase of development is currently underway.
Limitations of this study include the single-arm and open-label nature of the study with a small sample size.
This study was funded by AstraZeneca. Yang also reports having received past funding from Kazia Therapeutics, Plus Therapeutics, Debiopharm, Cantex Pharmaceuticals, and Biocept. He has also worked as an independent contractor for Galera Therapeutics, Nanocan Therapeutics, Kazia Therapeutics, Plus Therapeutics, and AstraZeneca. He has stock options in Nanocan Therapeutics.
Abstract
Session Title: Novel Agents and Emerging Therapeutic Strategies Location: Hall GH – Ground Level – Convention Center
Session Time:Tuesday, April 9, 2024, 2:30 pm – 4:30 pm Presentation CT043
Number:
Poster Board
Number:
Publishing Safety and preliminary efficacy of AZD1390 + radiation therapy (RT) for glioblastoma Title: (GBM)
J. T. Yang1, P. Wen2, B. S. Imber1, J. Drappatz3, R. Jena4, D. Forst5, A. Zukas6, S. C. Short7, C. Fan8, W. Trigg9, A. Milner9, U. Polanska10, C. Glover9, C. Stavraka9, D. Dalal11, D. Karanovic8, A. J. Chalmers12;
1Memorial Sloan Kettering Cancer Center, New York, NY, 2Center for Neuro-oncology, Dana-Farber Cancer Institute, Boston, MA, 3University of Pittsburgh Medical Center,
Author Block: Pittsburgh, PA, 4University of Cambridge, Cambridge, United Kingdom, 5Massachusetts General Hospital, Boston, MA, 6Medical University of South Carolina, Charleston,
SC, 7Leeds Institute of Medical Research at St. James’s, Leeds, United
Kingdom, 8AstraZeneca, Gaithersburg, MD, 9AstraZeneca, Cambridge, United Kingdom, 10AstraZeneca, Warsaw, Poland, 11AstraZeneca, New York, NY, 12School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
an encouraging median overall
survival (OS) of 12.7 months was observed in Arm A patients at doses demonstrating target engagement
Abstract Body:
Objective:
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 RT (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
AZD1390 With Radiotherapy Shows Manageable Safety Profile and Preliminary Efficacy for Patients with Glioblastoma in Phase I Trial
Page 3 of 3
(NCT05182905). This global, Phase 1, open-label study (NCT03423628) evaluates the safety and preliminary efficacy of escalating doses of AZD1390 and RT in pts with brain malignancies.
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, MGMT 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 Nov 15, 2023, 111 pts have received AZD1390 (75 in Arm A; 36 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 (53.2%), headache (38.7%) and nausea (38.7%). Grade ≥3 treatment-related AEs occurred in 18/111 pts (16.2%). 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 12.6% 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.
Conclusions:
Concurrent AZD1390 and IMRT administration is tolerated with a manageable safety profile, including 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.
