AZD6738 First time in patient Multiple Ascending Dose Study

Exclusion Criteria

• 1. Receiving, or having received during the four weeks prior to study entry (signing of consent), treatment for their malignancy.
• 2. Receiving, or having received during the four weeks prior to study entry (signing of consent), corticosteroids (at a dose > 10 mg prednisone/day or equivalent) for any reason.
• 3. A known hypersensitivity to AZD6738 or any excipient of the product.
• 4. Treatment with any investigational medicinal product (IMP) within 28 days prior to signing of consent.
• 5. Receiving, or having received, concomitant medications, herbal supplements and/or foods that significantly modulate CYP3A4 or Pgp activity (wash out periods of two weeks, but three weeks for St. John's Wort). Note these include common azole antifungals, macrolide antibiotics.
• 6. Impaired hepatic or renal function as demonstrated by any of the following laboratory values:
• a. Albumin < 33g/L
• b. AST or ALT > 2.5 x ULN
• c. Total bilirubin > 1.5 x ULN
• d. Alkaline phosphatase > 2.5 x ULN
• e. Glomerular filtration rate (GFR) < 50 mL/min, as assessed using the standard methodology at the investigating centre (i.e. Cockroft-Gault, MDRD or CKD-EPI formulae, EDTA clearance or 24 h urine collection)
• f. Serum creatinine > 1.5 x ULN
• g. Haematuria: +++ on microscopy or dipstick
• h. AST, ALT, ALP, bilirubin or renal function that, in the opinion of the investigator, is unstable or worsening
• 7. INR > 1.5 or other evidence of impaired hepatic synthesis function Persisting (> 8 weeks) severe pancytopenia due to previous therapy rather than disease (ANC < 0.5 x 109/L or platelets < 50 x 109/L) - to be confirmed via bone marrow biopsy, as part of normal clinical care, prior to signing of consent
• 8. CNS involvement with malignancy
• 9. Cardiac dysfunction as defined as: Myocardial infarction within six months of study entry, NYHA Class II/III/IV heart failure, unstable angina, unstable cardiac arrhythmias or reduced LVEF < 55%
• 10. Any of the following cardiac criteria:
• a. Mean resting corrected QT interval (QTc) >470 msec obtained from 3 electrocardiograms (ECGs) in 24 hours
• b. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block)
• c. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, immediate family history of long QT syndrome or unexplained sudden death under 40 years of age
• 11. Patients at risk of brain perfusion problems, e.g., carotid stenosis
• 12. Patients with relative hypotension (< 100/60 mm Hg) or clinically relevant orthostatic hypotension, including a fall in blood pressure of >20mm Hg
• 13. Uncontrolled hypertension requiring clinical intervention
• 14. Any other malignancy which has been active or treated within the past three years, with the exception of cervical intra-epithelial neoplasia and non-melanoma skin cancer
• 15. Refractory nausea and vomiting, chronic gastrointestinal diseases or previous significant bowel resection that would preclude adequate absorption of AZD6738
• 16. Patients with uncontrolled seizures
• 17. Active infection requiring systemic antibiotics, antifungal or antiviral drugs
• 18. Concurrent severe and/or uncontrolled medical condition (e.g., severe COPD, severe Parkinson's disease, active inflammatory bowel disease) or psychiatric condition