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

NCT03423628 | Recruiting Phase 1 FDA Drug

• 3 other identifiers: D6940C000021358032017-002451-28
• Study Type: interventional
• Target: 180
• Locations: 3 countries
• Sites: 12

Brief Summary

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

Conditions

Recurrent Glioblastoma Multiforme; Primary Glioblastoma Multiforme; Brain Neoplasms, Malignant; Leptomeningeal Disease (LMD)

Keywords

glioblastoma; Ataxia-telangiectasia mutated kinase (ATM) inhibition; radiation therapy

Outcome Measures

Primary Outcomes (2)

• 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

  From the start of treatment until the end of the DLT period (approximately 6 weeks for Arm A, 3 weeks for Arm B and 10 weeks for Arm C)

• 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.

  From the start of treatment until the end of the study (approximately 9 months after the last patient has started treatment)

Secondary Outcomes (9)

• Event free survival (EFS) for Arms A and C only

  From the start of treatment until the patient is off study (approximately 9 months after the last patient has started treatment)

• Objective response rate defined by RANO criteria for Arms A and C only

  Every 8 weeks starting from 4 weeks after RT until the end of the study (approximately 9 months after the last patient has started treatment)

• Objective response rate defined by RANO-BM criteria for Arm B only. **Arm B has now closed to recruitment**

  From screening until the patient is off study, approximately 8 weeks

• Objective response rate defined by RECIST 1.1 criteria for Arm B only. **Arm B has now closed to recruitment**

  From screening until the patient is off study, approximately 8 weeks

• Maximum Observed Plasma Concentration (Cmax) of AZD1390

  At predefined intervals throughout the AZD1390 treatment period (approximately 5 weeks for Arm A, 2 weeks for Arm B and 9 weeks for Arm C)

Study Arms (3)

Arm A: AZD1390 + Radiation Therapy

EXPERIMENTAL

AZD1390 administration plus 35 Gy of Intensity-modulated radiation therapy (IMRT) administered at daily fractions of 3.5 Gy over 10 fractions (2 weeks)

Radiation: Radiation Therapy; Drug: AZD1390

Arm B: AZD1390 + Radiation Therapy

EXPERIMENTAL

AZD1390 administration plus 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).

Radiation: Radiation Therapy; Drug: AZD1390

Arm C: AZD1390 + Radiation Therapy

EXPERIMENTAL

AZD1390 administration plus 60 Gy of intensity- modulated radiation therapy (IMRT) administered at daily fractions of 2 Gy over 30 fractions (6 weeks)

Radiation: Radiation Therapy; Drug: AZD1390

Interventions

AZD1390 DRUG

AZD1390 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.

Also known as: ATM inhibitor

Arm A: AZD1390 + Radiation Therapy

Radiation Therapy RADIATION

35 Gy of Intensity-modulated radiation therapy (IMRT) administered at daily fractions of 3.5 Gy over 10 fractions (2 weeks)

Also known as: Radiotherapy, Radiation treatment, RT

Arm A: AZD1390 + Radiation Therapy

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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 administration.
• \*\*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 metastases

You may not qualify if:

• 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 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 (For Japan part only this includes active infection including tuberculosis, chronic active or uncontrolled Hep B or Hep C)
• Has previously received ATM inhibitor with concurrent RT
• Diabetes Type I, Type II, or steroid-induced diabetes.
• Undergoing systemic steroid treatment \*Note: the food effect assessment is currently open to enrolment\*

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (12)

Research Site

Boston, Massachusetts, 02114, United States

RECRUITING

Research Site

Boston, Massachusetts, 02215, United States

RECRUITING

Research Site

New York, New York, 10065, United States

RECRUITING

Research Site

Pittsburgh, Pennsylvania, 15232, United States

RECRUITING

Research Site

Richmond, Virginia, 23298, United States

RECRUITING

Research Site

Chūōku, 104-0045, Japan

COMPLETED

Research Site

Hidaka-shi, 350-1298, Japan

ACTIVE NOT RECRUITING

Research Site

Kyoto, 606-8507, Japan

ACTIVE NOT RECRUITING

Research Site

Cambridge, CB2 0QQ, United Kingdom

ACTIVE NOT RECRUITING

Research Site

Glasgow, G12 0YN, United Kingdom

COMPLETED

Research Site

Leeds, LS9 7TF, United Kingdom

RECRUITING

Research Site

London, W1T 7HA, United Kingdom

WITHDRAWN

MeSH Terms

Conditions

Glioblastoma; Brain Neoplasms; Meningeal Neoplasms; Hereditary Sensory and Autonomic Neuropathies; Inhibition, Psychological

Interventions

Radiotherapy; AZD1390

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Nervous System Malformations; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Behavior

Intervention Hierarchy (Ancestors)

Therapeutics

Study Officials

• Patrick Wen

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

• Brandon Imber

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

• Mariza Daras

  VCU Massey Cancer Center

  PRINCIPAL INVESTIGATOR

• Jan Drappatz

  UPMC Hospital Radiation Oncology

  PRINCIPAL INVESTIGATOR

• Deborah Forst

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

• Anthony Chalmers

  Beatson West of Scotland Cancer Centre

  PRINCIPAL INVESTIGATOR

• Rajesh Jena

  Cambridge University Hospitals NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

• Louise Murray

  University of Leeds

  PRINCIPAL INVESTIGATOR

• Yoshitaka Narita

  National Cancer Center Hospital

  PRINCIPAL INVESTIGATOR

• Yoshiki Arakawa

  Kyoto University Hospital

  PRINCIPAL INVESTIGATOR

• Kazuhiko Mishima

  Saitama Medical University International Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

AstraZeneca Clinical Study Information Center

CONTACT

1-877-240-9479; information.center@astrazeneca.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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 food effect assessment is currently open to recruitment\*

Study Record Dates

• First Submitted: November 28, 2017
• First Posted: February 6, 2018
• Study Start: April 2, 2018
• Primary Completion (Estimated): September 16, 2026
• Study Completion (Estimated): September 16, 2026
• Last Updated: December 22, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

US (5); JP (3); GB (4)