A Phase I Study of Safety, Tolerability, and PK of AZD2811 in Patients With Advanced Solid Tumors.

This is a first-time-in-patient (FTIP) study with the nanoparticle formulation of AZD2811
primarily designed to evaluate the safety and tolerability of AZD2811 at increasing doses in
patients with advanced solid tumours and for whom no standard of care exists.

The study will be conducted in two parts: Part A dose-escalation and Part B dose-expansion.
In Part A, the dose-escalation phase, patient enrolment has proceeded according to a 3+3
design in order to identify the maximum-tolerated dose (MTD) or recommended Phase 2 dose
(RP2D). AZD2811 monotherapy has been administered IV to patients with advanced solid tumours
on Days 1 and 4 of a 28-day cycle in 6 dose levels without any relevant toxicities in the
first 5 patient cohorts. In Cohort 6 (200 mg), grade 4 asymptomatic neutropenia was observed,
and a dose-limiting toxicity was observed in 1 patient of the 5 evaluable patients. In Cohort
7 AZD2811 (200 mg) was given on Day 1 only of a 28-day cycle; in Cohort 8 AZD2811 (200 mg)
was given on Day 1 only of a 21-day cycle. In Cohort 9, the AZD2811 dose was escalated to 400
mg on Day 1 every 21 days.

The Safety Review Committee (SRC) will review the safety and tolerability of AZD2811 for each
cohort and schedule to determine the next cohorts. The study will also characterize the
pharmacokinetic (PK) profile of AZD2811 and will explore potential biological activity by
assessing anti-tumour activity in patients.

Once the MTD is established, Part B the dose expansion phase will continue to explore PK
parameters, safety, tolerability, and preliminary anti-tumour activity of the AZD2811 RP2D as
monotherapy in 21 patients with relapsed/refractory SCLC.

Inclusion Criteria:

Part A Dose Escalation:

1. Histological or cytological confirmation of a solid tumour and disease progression
despite standard therapy(ies), or they must be intolerant to standard therapy(ies), or
no standard therapy exists.

2. Patients must have received ≤3 prior chemotherapy regimens in the metastatic setting
which may have included irinotecan.

Part B Dose Expansion:

1. Patients must have received at least 1 prior platinum-based systemic therapy but no more
than 3 prior systemic regimens for relapsed and/or refractory SCLC.

Inclusion Criteria All Patients:

1. Measurable or non-measurable (but evaluable disease) according to RECIST v1.1.

2. Age ≥18

3. Adequate organ system functions, as outlined by a) absolute neutrophil count (ANC)
≥1.5 X 10^9/L, b) platelets ≥100 X 10^9/L, c) hemoglobin ≥9 g/dL, d) PT/PTT/INR ≤1.5 x
upper limit of normal (ULN), e) total bilirubin ≤1.5 mg/dL, f) ALT and AST ≤3.0 times
the ULN if no liver involvement or ≤5 times the ULN with liver involvement, g)
creatinine ≤1.5 x ULN, OR calculated or measured creatinine clearance ≥50 mL/min, OR
24-hour measured urine creatinine clearance ≥50 mL/min

4. ECOG performance status 0-1.

5. Must provide an archived tissue sample for correlative testing, if available. If
archived tissue is not available, patient will still be eligible for enrolment into
the study.

6. Predicted life expectancy ≥12 weeks.

7. Females of child-bearing potential should be using adequate contraceptive measures
from the time of screening until 6 months after study discontinuation, should not be
breast feeding and must have a negative pregnancy test prior to start of dosing.
Females of non-child-bearing potential must have evidence by the following criteria at
screening: a) post-menopausal defined as aged > 50 and amenorrhoeic for at least 12
months following cessation of all exogenous hormonal treatments, b) documentation of
irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or
bilateral salpingectomy, but not tubal ligation, c) women < 50 would be considered
postmenopausal if they have been amenorrhoeic for > 12 months following cessation of
all exogenous hormonal treatments, and have serum follicle-stimulating hormone and
luteinizing hormone levels in the postmenopausal range.

8. Sexually active males should be willing to use barrier contraception (i.e., condoms).

Exclusion Criteria:

1. Patients who have been treated with most recent radiotherapy, immunotherapy,
chemotherapy or investigational drugs within ≤21 days or 5 half-lives (whichever is
shorter) from enrolment (screening), and/or who have any unresolved NCI Common
Terminology Criteria of Adverse Events (CTCAE) v4.03 > Grade 1 treatment-related side
effect, with the exceptions of alopecia, should not be enrolled.

2. Major surgery (excluding placement of vascular access) ≤21 days from beginning of the
study drug or minor surgical procedures ≤7 days. No waiting is required following
implantable port and catheter placement.

3. Previous treatment with alisertib.

4. Any of the following cardiac criteria: a) Congestive heart failure (CHF) per New York
Heart Association (NYHA) classification > Class II, b) Cardiac ventricular arrhythmias
requiring anti-arrhythmic therapy, c) Unstable angina or new-onset angina, d) QTcF
interval >470 ms on screening ECG.

5. Active non-infectious skin disease (including any grade rash, urticarial, dermatitis,
ulceration, or psoriasis, but excluding stable plaque psoriasis from the definition of
active disease).

6. Patients with diarrhoea NCI CTCAE v4.03 Grade ≥2.

7. Patient has had prescription or non-prescription drugs or other products known to be
strong inhibitors/inducers of CYP3A4 which cannot be discontinued prior to Day 1 of
dosing and withheld throughout the study until 2 weeks after the last dose of study
drug.

8. Any evidence of active infection, severe or uncontrolled systemic diseases including
uncontrolled hypertension, active bleeding diatheses, hepatitis B, hepatitis C and
human immunodeficiency virus.

9. Previously untreated brain metastases. Patients who have received radiation or surgery
for brain metastases are eligible if therapy was completed at least 3 weeks previously
and there is no evidence of central nervous system disease progression, mild
neurologic symptoms, and no requirement for chronic corticosteroid therapy.

10. Treatment with haematopoietic colony-stimulating factors (e.g., G-CSF) ≤2 weeks prior
to screening visit.

11. History of hypersensitivity to active or inactive excipients (e.g., PEG) of any drug
in the study or drugs with similar chemical structure or class to those being
investigated in the study.

12. Lactating, breastfeeding, or positive pregnancy test for female patients of
child-bearing potential.

13. Concurrent conditions that in the Investigator's opinion would jeopardize compliance
with the protocol.

14. Psychological, familial, sociological, or geographical conditions that do not permit
compliance with the protocol.