Treatment With AZD4547 for Recurrent Malignant Glioma Expressing FGFR-TACC Gene Fusion"

Inclusion criteria:

1. Recurrent glioma after standard treatment, expressing the FGFR3-TACC3 or FGFR1-TACC1 fusion gene as confirmed by RT-PCR sequencing.
2. First recurrence occurring more than three months from the end of the radiotherapy or occurring outside the irradiated volume.
3. World Health Organisation performance status 0-2 (KPS\>50) with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks.
4. Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses.

   If a patient declines to participate in any voluntary exploratory research component of the study, there will be no penalty or loss of benefit to the patient and he/she will not be excluded from other aspects of the study
5. Aged at least 18 years.
6. Patients should be using adequate contraceptive measures which should be maintained during the whole duration of AZD4547 treatment and at least 7 days after treatment suspension. Females should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:

   * Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments.
   * Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation

Exclusion criteria:

1. Treatment with any of the following:

   * Nitrosourea within 6 weeks before the first dose of study treatment
   * Any investigational agents or study drugs from a previous clinical study within 30 days before the first dose of study treatment
   * Any other chemotherapy, anticancer immunotherapy or anticancer agents within 4 weeks before the first dose of study treatment, except hormonal therapy.
   * Potent inhibitors or inducers of CYP3A4 or 2D6 or substrates of CYP3A4 within the required washout period as specified in the section 7.3
   * Prior treatment in this or another AZD4547 study, or prior randomisation in a study in which AZD4547 is/was under investigation. Prior treatment with any FGFR inhibitor.
2. Major surgery (excluding placement of vascular access) within 14 days before the first dose of study treatment
3. With the exception of alopecia, any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment
4. As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required
5. Any of the following cardiac criteria:

   * Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia's correction.Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block
   * Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval
   * History of myocardial infarction, unstable angina, stroke or transient ischemic attack within the last 6 months
6. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

   * Absolute neutrophile count \<1.5 x 109/L
   * Platelet count \<100 x 109/L
   * Haemoglobin \<90 g/L
   * Alanine aminotransferase \>2.5 times the upper limit of normal (ULN)
   * Aspartate aminotransferase \>2.5 times ULN Total bilirubin \>1.5 times ULN
   * Creatinine \>1.5 times ULN concurrent with creatinine clearance \<50 ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is \>1.5 times ULN
   * Corrected calcium \>ULN
   * Phosphate \>ULN
7. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD4547
8. History of hypersensitivity to active or inactive excipients of AZD4547 or drugs with a similar chemical structure or class to AZD4547
9. Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
10. Any of the following ophthalmological criteria:

    * Current evidence or previous history of retinal pigmented epithelium detachment (RPED)
    * Previous laser treatment or intra-ocular injection for treatment of macular degeneration
    * Current evidence or previous history of dry or wet age-related macular degeneration
    * Current evidence or previous history of retinal vein occlusion (RVO)
    * Current evidence or previous history of retinal degenerative diseases (eg, hereditary)
    * Current evidence or previous history of any other clinically relevant chorioretinal defect
11. Contraindications to MRI