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

NCT03423628

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

Related Conditions:
  • Glioblastoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study to Assess the Safety and Tolerability of AZD1390 Given With Radiation Therapy in Patients With Brain Cancer
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: D6940C00002
  • SECONDARY ID: 2017-002451-28
  • SECONDARY ID: 135803
  • NCT ID: NCT03423628

Conditions

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

Interventions

DrugSynonymsArms
AZD1390ATM inhibitorAZD1390 + Radiation Therapy

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
AZD1390 + Radiation TherapyExperimentalAZD1390 + Radiation Therapy
  • AZD1390

Eligibility Criteria

        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.

               -  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 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) 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.

          -  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 within past year. If prior therapy in lifetime,
             then excluded if history of pulmonary toxicities from administration.

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description:Defined as the time from the first dose of AZD1390 until the occurrence of any of the following events: Tumor progression or recurrence based on RANO criteria Secondary malignancy Change in tumor treatment due to increase clinical symptoms Death due to any cause
Measure: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)
Safety Issue:
Description:The proportion of patients achieving a complete or partial tumor response (CR or PR) according to RANO criteria.
Measure: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
Safety Issue:
Description:The proportion of patients achieving a complete or partial tumor response (CR or PR) according to RANO-BM criteria.
Measure: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
Safety Issue:
Description:The proportion of patients achieving a complete or partial tumor response (CR or PR) according to RECIST 1.1 criteria.
Measure: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)
Safety Issue:
Description:Blood samples will be collected to assess plasma concentrations of AZD1390 at a series of timepoints to derive Cmax
Measure: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)
Safety Issue:
Description:Blood samples will be collected to assess plasma concentrations of AZD1390 at a series of timepoints to derive Tmax
Measure: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)
Safety Issue:
Description:Blood samples will be collected to assess plasma concentrations of AZD1390 at a series of timepoints to derive AUC
Measure: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)
Safety Issue:
Description:Urine samples will be collected to assess urine concentrations of AZD1390 at a series of timepoints to derive renal clearance

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • glioblastoma
  • brain metastases
  • Ataxia-telangiectasia mutated kinase (ATM) inhibition
  • radiation therapy

Last Updated

February 5, 2018