Patient case: 50-year-old male with glioblastoma; genetic feature: IDH1 (R132H)

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

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.

Eligibility: 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

Relevance to patient case: not relevant