A Study to Assess the Safety and Tolerability of AZD1390 Given With Radiation Therapy in Patients With Brain Cancer

This first time-in patients (FTIP), open-label, multicentre study of AZD1390 will be
conducted in the United States and in the United Kingdom, and it consists of three treatment
arms: Arm A, B, C. This Phase 1 study will assess safety and tolerability of AZD1390 in
combination with radiation therapy (RT) in brain malignancies. The combination cohorts have
been designed to assess escalating cumulative doses of AZD1390 in settings with 3 different
radiation treatment regimens:

- Arm A: 35 Gy over 2 weeks with intensity-modulated radiation therapy (IMRT) in patients
with recurrent Glioblastoma Multiforme (GBM)

- Arms B: 30 Gy over two weeks with whole brain radiation therapy (WBRT) in patients with
brain metastases

- 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.

Inclusion Criteria:

- Provision of formalin-fixed paraffin embedded tissue sample from primary or metastatic
disease

- Karnofsky Performance Score of ≥60.

- Additional Inclusion Criteria Specific for Arm A:

- 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.

- Patients with tumor-induced seizures must be well controlled on a stable
anti-epileptic treatment

- Willing to receive anti-epileptic prophylaxis for the duration of study drug
administration.

- Additional Inclusion Criteria Specific for Arm B:

- 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.

- Non-central nervous system (CNS) malignant disease must be sufficiently
controlled so that patient can be without additional systemic therapy for
approximately 2 months

- Not received radiation to the lung fields within the past 8 weeks.

- No history of seizures related to the brain metastases or LMD.

- Additional Inclusion Criteria Specific for Arm C:

- 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.

- Willing to receive anti-epileptic prophylaxis for the duration of study drug
administration

Exclusion Criteria:

- 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.

- History of epileptic disorder or any seizure history unrelated to tumor

- Treatment with Strong inhibitors or inducers of CYP3A4 within 2 weeks prior to
receiving study drug

- 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.

- Cardiac dysfunction defined as: Myocardial infarction within six months of study
entry, NYHA (New York Heart Association) Class II/III/IV heart failure, unstable
angina, unstable cardiac arrhythmias

- Evidence of severe pulmonary infections, as judged by the investigator