This study will test an investigational drug called AZD1390 in combination with radiation therapy for the treatment of brain tumors. This is the first time AZD1390 is being given to patients. This study will test safety, tolerability and PK (how the drug is absorbed, distributed and eliminated) of ascending doses of AZD1390 in combination with distinct regimens of radiation therapy
Provision of formalin-fixed paraffin embedded tissue sample from primary or metastatic disease
Karnofsky Performance Score of ≥60.
Histologically proven diagnosis of GBM. Patients who have had RT for low-grade glioma (LGG) or grade 3 glioma and have subsequently relapsed to histologically confirmed GBM can be considered
A radiological diagnosis of recurrent/relapsed or progressive disease according to RANO criteria.
Administration of chemotherapy or any investigational drug in the 28 days or carmustine (CCNU) or lomustine (BCNU) in the 6 weeks prior to receiving the first dose of treatment in Arms A and C. Administration of checkpoint inhibitors within 28 days prior to first dose of treatment and any other agent within 7 days of beginning study treatment in Arm B. 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.
History of epileptic disorder or any seizure history unrelated to tumor
Single group
Radiation Therapy
Radiation35 Gy of Intensity-modulated radiation therapy (IMRT) administered at daily fractions of 3.5 Gy over 10 fractions (2 weeks)
AZD1390
DrugAZD1390 Administered in 3 Cycles depending on arm: Cycle 0: 1 dose prior to Radiation Therapy. Cycle 1: 2 weeks Intermittent or continuous dosing during Radiation Therapy. Cycle 2: 2 weeks adjuvant treatment after Radiation Therapy. For optional food effect assessment in Arm A, 2 doses prior to RT under both fed and fasted conditions. Note: the food effect assessment is currently open to recruitment. Arm A includes the Japan part following the same dosing administration.
Radiation Therapy
Radiation30 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).
Radiation Therapy
Radiation60 Gy of intensity- modulated radiation therapy (IMRT) administered at daily fractions of 2 Gy over 30 fractions (6 weeks)
AZD1390
DrugAZD1390 administered in 1 Cycle. AZD1390 administration concomitantly with RT (2 weeks). Cycle 1 also contains an additional 5 days (post completion of RT with AZD1390 administration). Arm is Closed.
AZD1390
DrugAZD1390 Administered in 3 Cycles depending on arm: Cycle 0: 1 dose prior to Radiation Therapy. Cycle 1: 6 weeks Intermittent or continuous dosing during Radiation Therapy. Cycle 2: 2 weeks adjuvant treatment after Radiation Therapy. Arm is closed.
Incidence of dose-limiting toxicities (DLTs)
DLTs will be used to calculate the maximum tolerated dose (MTD). In each arm, the MTD of AZD1390 is the highest dose at which the predicted probability of a DLT is less than 25% in that specific RT setting
Incidence of adverse events (AEs) and serious adverse events (SAEs)
For each adverse event CTCAE grade and causality (related to AZD1390 or radiotherapy) will be collected.
Event free survival (EFS) for Arms A and C only
Defined as the time from the first dose of AZD1390 until the occurrence of any of the following events: 1. Tumor progression or recurrence based on RANO criteria 2. Secondary malignancy 3. Change in tumor treatment due to increase clinical symptoms 4. Death due to any cause
Objective response rate defined by RANO criteria for Arms A and C only
The proportion of patients achieving a complete or partial tumor response (CR or PR) according to RANO criteria.
Objective response rate defined by RANO-BM criteria for Arm B only. **Arm B has now closed to recruitment**
The proportion of patients achieving a complete or partial tumor response (CR or PR) according to RANO-BM criteria.
Objective response rate defined by RECIST 1.1 criteria for Arm B only. **Arm B has now closed to recruitment**
The proportion of patients achieving a complete or partial tumor response (CR or PR) according to RECIST 1.1 criteria.
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