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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03423628
Recruitment Status : Recruiting
First Posted : February 6, 2018
Last Update Posted : February 11, 2020
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE November 28, 2017
First Posted Date  ICMJE February 6, 2018
Last Update Posted Date February 11, 2020
Actual Study Start Date  ICMJE April 2, 2018
Estimated Primary Completion Date April 5, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 5, 2018)
  • Incidence of dose-limiting toxicities (DLTs) [ Time Frame: From the start of treatment until the end of the DLT period (approximately 6 weeks for Arm A and B and 10 weeks for Arm C) ]
    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.
  • Incidence of adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: From the start of treatment until the patient is off study (approximately 1 year for Arm A and C and approximately 7 weeks for Arm B) ]
    For each adverse event CTCAE grade and causality (related to AZD1390 or radiotherapy) will be collected.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 5, 2018)
  • Event free survival (EFS) for Arms A and C only [ Time Frame: From the start of treatment until the patient is off study (approximately 1 year) ]
    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 [ Time Frame: Every 8 weeks starting from 4 weeks after RT until the end of the study (approximately 1 year) ]
    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 [ Time Frame: From screening until the patient is off study, approximately 8 weeks ]
    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 [ Time Frame: From screening until the patient is off study, approximately 8 weeks ]
    The proportion of patients achieving a complete or partial tumor response (CR or PR) according to RECIST 1.1 criteria.
  • Maximum Observed Plasma Concentration (Cmax) of AZD1390 [ Time Frame: At predefined intervals throughout the AZD1390 treatment period (approximately 5 weeks for Arms A and B and 9 weeks for Arm C) ]
    Blood samples will be collected to assess plasma concentrations of AZD1390 at a series of timepoints to derive Cmax
  • Time to observed Cmax (Tmax) for AZD1390 [ Time Frame: At predefined intervals throughout the AZD1390 treatment period (approximately 5 weeks for Arms A and B and 9 weeks for Arm C) ]
    Blood samples will be collected to assess plasma concentrations of AZD1390 at a series of timepoints to derive Tmax
  • Area under the plasma concentration-time curve (AUC) for AZD1390 [ Time Frame: At predefined intervals throughout the AZD1390 treatment period (approximately 5 weeks for Arms A and B and 9 weeks for Arm C) ]
    Blood samples will be collected to assess plasma concentrations of AZD1390 at a series of timepoints to derive AUC
  • Renal clearance (CLR) for AZD1390 [ Time Frame: At predefined intervals throughout the AZD1390 treatment period (approximately 5 weeks for Arms A and B and 9 weeks for Arm C) ]
    Urine samples will be collected to assess urine concentrations of AZD1390 at a series of timepoints to derive renal clearance
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Assess the Safety and Tolerability of AZD1390 Given With Radiation Therapy in Patients With Brain Cancer
Official Title  ICMJE 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
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
Detailed Description

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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Intervention Model Description:
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 each arm, AZD1390 will be administered in three cycles; Cycle 0 (before RT), Cycle 1 (during RT) and Cycle 2 (after 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.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Recurrent Glioblastoma Multiforme
  • Primary Glioblastoma Multiforme
  • Brain Neoplasms, Malignant
  • Leptomeningeal Disease (LMD)
Intervention  ICMJE
  • Radiation: Radiation Therapy

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

    Other Names:
    • Radiotherapy
    • Radiation treatment
    • RT
  • Drug: AZD1390

    AZD1390 Administered in 3 Cycles:

    Cycle 0: 1 dose prior to Radiation Therapy Cycle 1: Intermittent or continuous dosing during Radiation Therapy (except for first 2 cohorts of Arm A) Cycle 2: 2 weeks adjuvant treatment after Radiation Therapy

    Other Name: ATM inhibitor
Study Arms  ICMJE Experimental: AZD1390 + Radiation Therapy
AZD1390 + Radiation Therapy
Interventions:
  • Radiation: Radiation Therapy
  • Drug: AZD1390
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 5, 2018)
132
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 5, 2022
Estimated Primary Completion Date April 5, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 150 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Listed Location Countries  ICMJE United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03423628
Other Study ID Numbers  ICMJE D6940C00002
2017-002451-28 ( EudraCT Number )
135803 ( Registry Identifier: IND )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account AstraZeneca
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP