Arm C: 60 Gy over 6 weeks (IMRT) in patients with primary GBM Each arm provides standard of care RT for the disease setting indicated with the experimental agent being administered in dose escalating cohorts.
Intervention Model Description: AZD1390 will be administered to patients in three different Arms (A, B and C), with each arm receiving standard of care radiation therapy (RT) for their disease setting. In each arm, AZD1390 will be administered in three cycles; Cycle 0 (before RT), Cycle 1 (during RT) and Cycle 2 (after RT). Within each arm, AZD1390 will be administered in dose escalating cohorts, first in an intermittent and then in a consecutive fashion, to achieve daily administration prior to RT.
Arm A: 35 Gy of Intensity-modulated radiation therapy (IMRT) administered at daily fractions of 3.5 Gy over 10 fractions (2 weeks) Arm B: 30 Gy of whole brain radiation therapy (WBRT) or partial brain radiation therapy (PBRT) administered at daily fractions of 3 Gy over 10 fractions (2 weeks).
DLTs will be used to calculate the maximum tolerated dose (MTD). The MTD of AZD1390 is the maximum dose at which <=25% patients experience a DLT.
For each adverse event CTCAE grade and causality (related to AZD1390 or radiotherapy) will be collected.
The proportion of patients achieving a complete or partial tumor response (CR or PR) according to RANO criteria.
The proportion of patients achieving a complete or partial tumor response (CR or PR) according to RANO-BM criteria.
The proportion of patients achieving a complete or partial tumor response (CR or PR) according to RECIST 1.1 criteria.
Karnofsky Performance Score of ≥60.
Histologically proven diagnosis of GBM. Patients who have had RT for low-grade glioma (LGG) and have subsequently relapsed to histologically confirmed GBM can be considered for inclusion in Arm A after discussion with the Medical Monitor.
A radiological diagnosis of recurrent/relapsed or progressive disease according to RANO criteria.
Completion of first-line radiation at least 6 months prior to study entry.
Willing to receive anti-epileptic prophylaxis for the duration of study drug administration.
Histologically proven diagnosis of solid tumor malignancy and Magnetic Resonance (MR) imaging documenting brain lesions.
Not eligible for Stereotactic Radiosurgery (SRS) treatment of brain tumor.
Patient has not received any previous brain RT.
Not received radiation to the lung fields within the past 8 weeks.
No history of seizures related to the brain metastases or LMD.
Histologically proven primary diagnosis of GBM with unmethylated O6-methylguanine-DNA methyltransferase (MGMT).
Determination of MGMT promoter status by methylation-specific polymerase chain reaction (PCR) or pyrosequencing per local institutional guidelines is required to assess eligibility for this Arm.
Patients will have to undergo mutational testing for Isocitrate dehydrogenase 1 (IDH1) on a tumor specimen before entering study. Patients are eligible for Arm C regardless of their IDH1 mutational status.
No history of uncontrolled seizures after surgery for primary GBM (despite adequate antiepileptic therapy) or with need for concurrent administration of more than 2 antiepileptic drugs.
Administration of chemotherapy or any investigational drug in the 28 days prior to receiving the first dose of treatment. Hormonal therapies are allowed during study treatment for patients in Arm B.
History of severe brain-injury or stroke.
Patient not eligible for sequential MRI evaluations are not eligible for this study.
Concurrent therapy with other seizurogenic medications.
Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
Concurrent severe and/or uncontrolled medical condition (e.g., severe COPD).
Prior treatment with pneumotoxic drugs, e.g. busulfan, bleomycin, within the past year. If prior therapy in lifetime, then excluded if history of pulmonary toxicities from administration. Patients who have received treatment with nitrosoureas (e.g., carmustine, lomustine) in the year before study entry without experiencing lung toxicity are allowed on study.
History or presence of myopathy or raised creatine kinase (CK) >5 x upper limit of normal (ULN) on 2 occasions at screening.