AZD5363 in Patients With Advanced Solid Tumors Harboring AKT Mutations

Inclusion Criteria:

- Pathologically confirmed recurrent or metastatic advanced solid tumor, for which there
is no curative-intent treatment option and confirmation of the presence of AKT1, AKT2,
or AKT3 mutations detected by the MSK-IMPACT assay platform or other CLIA-approved
test

- ER+ breast cancer patients must have received and progressed on Fulvestrant and be
post-menopausal

- Prostate cancer patients must have received and progressed on enzalutamide

- Age ≥ 18 years

- ECOG performance status ≤ 1

- Life expectancy of ≥ 12 weeks

- Measurable disease as defined by the tumor specific relevant response criteria for the
breast and other solid tumor cohorts (measurable disease is not required for
enrollment in the prostate cancer cohort):

- RECIST version 1.1 criteria

- Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria.

- RANO criteria

- Females should be using adequate contraceptive measures (see Section 0), 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 amenorrhoeic for at least 12 months following
cessation of all exogenous hormonal treatments

- Estradiol, FSH and LH levels in post-menopausal range while receiving LHRH
analogues for medical castration in patients with breast cancer.

- Documentation of irreversible surgical sterilisation by hysterectomy, bilateral
oophorectomy or bilateral salpingectomy but not tubal ligation.

- Male patients should be willing to use barrier contraception (i.e. condoms)

Exclusion Criteria:

- ER+ breast cancer patients harboring the AKT1 E17K mutation (patient population tested
in MSK IRB# 14-214, study D3610C00001 part E, ClinicalTrials.gov NCT01226316).

- Diabetes mellitus type 1

- Fasting plasma glucose [fasting is defined as no calorific intake for at least 8
hours]:

- ≥ 126 mg/dL for those patients without a pre-existing diagnosis of Type 2
diabetes mellitus

- ≥ 167mg/dL for those patients with a pre-existing diagnosis of Type 2 diabetes
mellitus

- Glycosylated haemoglobin (HbA1C) ≥8.0%

- Requirement for insulin for routine diabetic management and control

- Requirement for >2 oral hypoglycaemic medications for routine diabetic management and
control

- Treatment with any of the following:

- Any investigational agents or study drugs from a previous clinical study within
30 days of the first dose of study treatment

- Any other chemotherapy, immunotherapy or anticancer agents within 3 weeks or 5
half lives, whichever is shorter, of the first dose of study treatment, except
fulvestrant, enzalutamide or hormonal therapy with LHRH analogues for medical
castration in patients with breast or prostate cancer, which are permitted

- Potent inhibitors or inducers or substrates of CYP3A4 or substrates of CYP2D6
within 2 weeks before the first dose of study treatment (3 weeks for St John‟s
Wort).

- Major surgery (excluding placement of vascular access) within 4 weeks of the
first dose of study treatment

- Radiotherapy with a wide field of radiation within 4 weeks of the first dose of
study treatment

- Prior ATP-competitive AKT inhibitors

- 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

- Spinal cord compression or brain metastases unless asymptomatic, treated and stable
and not requiring steroids for at least 4 weeks prior to start of study treatment

- As judged by the investigator, any evidence of severe or uncontrolled systemic
diseases, including active bleeding diatheses, or active infection including hepatitis
B, hepatitis C and human immunodeficiency virus. Screening for chronic conditions is
not required.

- Any of the following cardiac criteria:

- Resting corrected QT interval (QTc) > 480 msec obtained from electrocardiogram
(ECG)

- Any clinically important abnormalities in rhythm, conduction or morphology of
resting electrocardiogram (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

- Experience of any of the following procedures or conditions in the preceding 6
months: coronary artery bypass graft, angioplasty, vascular stent, myocardial
infarction, angina pectoris, congestive heart failure New York Heart Association
(NYHA) Grade ≥2

- Uncontrolled hypotension - Systolic blood pressure (BP) <90mmHg and/or diastolic
BP <50mmHg

- Left ventricular ejection fraction (LVEF) below lower limit of normal for site.

- Inadequate bone marrow reserve or organ function as demonstrated by any of the
following laboratory values:

- Absolute neutrophil count < 1 x 10^9/L

- Platelet count < 100 x 10^9/L

- Haemoglobin < 9.0 g/dL

- ALT > 2.5 times the upper limit of normal (ULN) if no demonstrable liver
metastases, or >5 times ULN in presence of liver metastases

- AST > 2.5 times ULN if no demonstrable liver metastases, or >5 times ULN in
presence of liver metastases.

- Total bilirubin > 1.5 times ULN (patients with confirmed Gilbert‟s syndrome may
be included in the study)

- Creatinine >1.5 times ULN concurrent with creatinine clearance < 50 ml/min;
confirmation of creatinine clearance is only required when creatinine is > 1.5
times ULN

- Proteinuria 3+ on dipstick analysis or >500 mg/24 hours

- Sodium or potassium outside normal reference range for site

- Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow the formulated product or previous significant bowel resection that would
preclude adequate absorption of AZD5363

- History of hypersensitivity to active or inactive excipients of AZD5363, fulvestrant
and enzalutamide or drugs with a similar chemical structure or class to these agents.

- 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