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Neuroepithelioma

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).

\*\*Arm B has now closed to recruitment\*\* Arm C: 60 Gy of intensity-modulated radiation therapy (IMRT) administered at daily fractions of 2 Gy over 30 fractions (6 weeks)

Radiation Therapy

AZD1390 Administered in 3 Cycles depending on arm:

Cycle 0 (arms A and C): 1 dose prior to Radiation Therapy. For optional food effect assessment in Arm A, 2 doses prior to RT under both fed and fasted conditions. \*Note: the optional food effect assessment is currently not open to recruitment\*.

Cycle 1 (all arms): Intermittent or continuous dosing during Radiation Therapy (except for first 2 cohorts of Arm A).

Cycle 2 (arms A and C): 2 weeks adjuvant treatment after Radiation Therapy.

AZD1390

AstraZeneca Clinical Study Information Center

Patrick Wen

Brandon Imber

Mariza Daras

Jan Drappatz

Deborah Forst

Anthony Chalmers

Rajesh Jena

Susan Short

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

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)/ partial brain radiation therapy (PBRT) in patients with brain metastases. \*\*Arm B has now closed to recruitment\*\*
* 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.

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 arms A and C, AZD1390 will be administered in three cycles: Cycle 0 (before RT), Cycle 1 (during RT) and Cycle 2 (after RT).

In arm B, AZD1390 will be administered in cycle 1 only (during 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 B has now closed to recruitment\*\*

For Arm A, there is an optional food effect assessment during cycle 0. \*Note: the optional food effect assessment is currently not open to recruitment\*

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

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.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

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.

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

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.

Blood samples will be collected to assess plasma concentrations of AZD1390 at a series of timepoints to derive Cmax

Blood samples will be collected to assess plasma concentrations of AZD1390 at a series of timepoints to derive Tmax

Blood samples will be collected to assess plasma concentrations of AZD1390 at a series of timepoints to derive AUC

Urine samples will be collected to assess urine concentrations of AZD1390 at a series of timepoints to derive renal clearance

Defined as the time from the first dose of AZD1390 until death from any cause

Spots Global Cancer Trial Database for primary glioblastoma multiforme