AZD6738 First Time in Patient Multiple Ascending Dose Study

In this first time in patient study, AZD6738 will be administered to patients with
relapsed/refractory chronic lymphocytic leukaemia (CLL), prolymphocytic leukaemia (PLL) or B
cell lymphomas, primarily to determine the safety and tolerability of AZD6738.
Pharmacokinetics of AZD6738 and potential biological activity will also be investigated.

An oral formulation of AZD6738 will be used. The starting dose of 20 mg twice daily (BD)
will be escalated to reach a maximum tolerated dose in patients as defined by dose-limiting
toxicity. A '3 week on, 1 week off' schedule, as deemed optimal in modelling of data from
non-clinical studies, will be used initially.

Following the dose escalation phase of the study, additional patients with prospectively
identified 11q-deleted or ATM deficient relapsed/refractory CLL will be enrolled to a dose
expansion phase to explore further the safety, tolerability, pharmacokinetics and biological
activity at selected dose(s)/schedule(s).

Inclusion Criteria:

1. Provision of signed and dated, written informed consent prior to any study specific
procedures, sampling and analyses.

2. For the dose escalation phase, Part A, histological or cytological confirmation of
relapsed or refractory B cell malignancy, including CLL, PLL, Burkitt
lymphoma/Burkitt cell leukaemia, acute lymphocytic leukaemia, hairy cell leukaemia
(HCL) and aggressive and indolent B cell lymphoma, not considered to be appropriate
for further conventional treatment.

For the dose expansion phase, Part B, histological or cytological confirmation of
relapsed or refractory 11q-deleted or ATM-deficient CLL, not considered to be
appropriate for further conventional treatment.

3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 with no
deterioration over the previous 2 weeks and an estimated life expectancy of greater
than 16 weeks.

4. Not known to be positive for HIV antibody, Hepatitis B surface antigen and Hepatitis
C antibody.

5. Females must be using adequate contraceptive measures, must 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 amenorrhoeic 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.

- Amenorrhoeic for 12 months and serum follicle-stimulating hormone (FSH),
luteinizing hormone (LH) and plasma oestradiol levels in the postmenopausal
range for the institution.

6. Ability to swallow and retain oral medication

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:

1. Albumin < 33g/L

2. AST or ALT > 2.5 x ULN

3. Total bilirubin > 1.5 x ULN

4. Alkaline phosphatase > 2.5 x ULN

5. 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)

6. Serum creatinine > 1.5 x ULN

7. Haematuria: +++ on microscopy or dipstick

8. 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:

1. Mean resting corrected QT interval (QTc) >470 msec obtained from 3
electrocardiograms (ECGs) in 24 hours

2. Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG (e.g., complete left bundle branch block, third degree heart block)

3. 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