A Phase I, Multicentre Study to Assess the Safety, Tolerability, and Pharmacokinetics of Ascending Doses of AZD1390 in Combination with Radiation Therapy in Patients with Glioblastoma Multiforme and Brain Metastases from Solid Tumors

Protocol # :
Recurrent Glioblastoma Multiforme
Primary Glioblastoma Multiforme
Brain Neoplasms, Malignant
Leptomeningeal Disease (LMD)
Disease Sites
Brain and Nervous System
Principal Investigator
Wen, Patrick, Yung
Site Investigator
Forst, Deborah
Site Research Nurses
Aste, Marie, Francesca
Chau, Johny, E.

Trial Description

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

Eligibility Requirements

Inclusion Criteria:

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

- 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) 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.

- Completion of first-line radiation at least 6 months prior to Cycle 1 Day 1.

- 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

- Additional Inclusion Criteria Specific for Arm B:

**Arm B has now closed to recruitment**

- 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 to the area that is to be irradiated.
Prior PBRT may be allowed if there is not significant overlap between the prior and
new radiation fields.

- Non-CNS malignant disease must be sufficiently controlled so that patients can be
without additional systemic therapy for the required washout period before starting
therapy until 5 days after the end of RT. Required washout period before starting the
first dose of AZD1390 (Cycle 1) is 28 days for immune checkpoint inhibitors and 7 days
for all other agents

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

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

- Receiving PBRT (rather than WBRT) during Cycle 1 as standard of care for brain

• Additional Inclusion Criteria Specific for Arm C:

- Histologically proven primary diagnosis of GBM with unmethylated O6-methylguanine-DNA
methyltransferase (MGMT). Grade 4 astrocytoma or histology with molecular features of
GBM can be considered.

- 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

Additional Inclusion criteria for Food Effect Assessment (Arm A):

- For the fed assessment portion: fast overnight (for at least 10 hours) prior to
consuming a high-fat meal consisting of approximately 800 to 1000 calories, with
around 54% of the calories coming from fat.

- For the fasted assessment portion: fast overnight (for at least 10 hours prior to
dosing) and until 4 hours after dosing.

*Note: the optional food effect assessment is currently not open to enrolment*

Exclusion 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

- 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

- 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

- With the exception of alopecia, any unresolved toxicities from prior therapy greater
than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI
CTCAE 4.03) Grade 1 at the time of starting study treatment and patients with chronic
Grade 2 unresolved toxicities may be eligible

Additional Exclusion criteria for Food Effect Assessment (Arm A):

- Diabetes Type I, Type II, or steroid-induced diabetes.

- Undergoing systemic steroid treatment *Note: the optional food effect assessment is
currently not open to enrolment*