Safety, Tolerability, Pharmacokinetics, and Efficacy of AZD2811 Nanoparticles as Monotherapy or in Combination in Acute Myeloid Leukemia Patients.

This is a Phase I/II clinical study to determine the maximum tolerated dose (MTD), safety,
tolerability, pharmacokinetics, and pharmacodynamics of AZD2811 with or without azacytidine
in patients with relapsed AML or treatment-naïve AML patients not eligible for intensive
induction therapy. The study will also explore the potential clinical activity by assessing
anti-tumour activity in patients. The study will be conducted in two parts, designated Part
A, dose escalation, and Part B, dose expansion.

Part A - Dose Escalation

Monotherapy Escalation: Approximately 36 evaluable treatment-naïve AML patients not eligible
for intensive induction therapy or relapsed/refractory AML patients will be enrolled in the
monotherapy escalation in Part A of this study.

The dose escalation and de-escalation plan for evaluating AZD2811 will follow the Bayesian
Adaptive Design scheme which combines prior expectations about the dose toxicity relationship
and applies the data at the end of each cohort to recommend a dose for the next cohort. The
total number of patients will depend upon the number of dose escalations/de-escalations
necessary. At least 3 and up to 6 evaluable patients will be required for each dose cohort.
Patients will receive a single 2- or 4- hour IV infusion on Day 1 and Day 4 of each 28-day
cycle. Dosing frequency and schedule may be adjusted during the study on the basis of
emerging safety and pharmacokinetic data.

Combination Escalation: The dose of AZD2811 chosen for investigation in combination with the
standard dose of the hypomethylating agent (HMA) azacitidine will not exceed the dose that
was found tolerable as monotherapy. In this dose escalation part, approximately 12-15
evaluable treatment-naïve AML patients not eligible for intensive induction therapy or
relapsed/refractory AML will be enrolled and dosed in ascending doses of AZD2811 and standard
dose of azacitidine at 75 mg/m² subcutaneously (SC) or by IV. AZD2811 will be administered
over 2 hours for doses up to and including 600 mg and over 4 hours for doses exceeding 600 mg
on Days 1 and 4 of each 28-day cycle. Patients will receive 75 mg/m² of azacitidine on Days 1
through 7 or for 5 consecutive weekdays (Days 1 through 5) with a treatment holiday on the
two weekend days (Days 6 and 7), and azacitidine dosing on the first 2 weekdays of the next
week (Days 8 and 9) of each 28-day cycle.

The combination group will use a rolling 6 method which allows accrual of 2 to 6 patients
concurrently onto a dose level based on the numbers of patients who are currently enrolled
and evaluable, who experience a DLT, and who remain at risk of developing a DLT.

Part B - Dose Expansion

Part B will include up to 80 treatment-naïve AML patients not eligible for intensive
induction therapy at the MTD in AZD2811 monotherapy (Group 1, 40 patients) and AZD2811 in
combination with azacitidine (Group 2, 40 patients) in order to further explore the
tolerability, PK and clinical activity at this dose.

Inclusion Criteria for All Patients:

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

2. ≥ 18 years of age

3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.

4. Prior treatment with hydroxyurea (up to 24 hours before study treatment) is allowed.

5. Adequate organ system function as outlined below:

- PT/PTT ≤1.5 x upper limit of normal (ULN)

- Total bilirubin ≤1.5 x ULN. Patients with documented Gilbert's Syndrome who have
serum bilirubin ≤3 x the ULN may be enrolled, unless there is evidence of
hemolytic anemia

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ˂2.5 × ULN if
no liver involvement or ≤5 times the ULN with liver involvement

- Creatinine ≤1.5 x ULN, OR calculated or measured creatinine clearance ≥50 mL/min
as calculated by the Cockcroft-Gault method, OR 24-hour measured urine creatinine
clearance ≥50 mL/min

6. Other comorbidity that the Investigator judges incompatible with intensive remission
induction chemotherapy, which must be documented by the study monitor.

7. Females should be using adequate contraception, 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

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

8. Sexually active male patients should be willing to use barrier contraception i.e.,
condoms. Female partners of male patients should also use a highly effective form of
contraception if they are of childbearing potential, unless the male patient is
abstaining from sexual intercourse.

Part A (Dose Escalation) Inclusion Criteria:

1. AML patients who have relapsed or are refractory to standard therapies.

2. AML patients who are unlikely to demonstrate rapid progression such that they would be
unable to complete the first cycle of therapy.

3. Adults with previously untreated confirmed diagnosis of AML (bone marrow blasts ≥ 20%)
for whom monotherapy with AZD2811 is considered appropriate and are not suitable for
intensive induction therapy based on the following:

- ≥75 years, or

- <75 years of age with clinically significant cardiac or pulmonary dysfunction
unrelated to leukaemia, as reflected by at least 1 of the following criteria:

- Left ventricular ejection fraction (LVEF) ≤50%

- Diffusing capacity of the lungs for carbon monoxide (DLCO) ≤65% of expected

- Forced expiratory volume 1 (FEV1) ≤65% of expected

- Chronic stable angina

Part B (Dose Expansion) Inclusion Criterion

1. Adults with previously untreated confirmed diagnosis of AML per World Health
Organization (WHO) and European Leukemia Net (ELN) criteria (bone marrow blasts ≥ 20%) who
are not suitable for intensive induction therapy based on the following:

- ≥75 years, or

- <75 years of age with clinically significant cardiac or pulmonary dysfunction
unrelated to leukaemia, as reflected by at least 1 of the following criteria:

- Left ventricular ejection fraction (LVEF) ≤50%

- Diffusing capacity of the lungs for carbon monoxide (DLCO) ≤65% of expected

- Forced expiratory volume 1 (FEV1) ≤65% of expected

- Chronic stable angina

Exclusion Criteria:

Patients must not enter the study if any of the following exclusion criteria are fulfilled

1. Treatment with any of the following:

- Any investigational agents, experimental antibody or antibody drug conjugates, or
study drugs from a previous clinical study within 3-4 weeks of said prior
investigational agent(s) with regard to the first dose of study treatment on this
protocol.

- Any other chemotherapy, immunotherapy or anticancer agents within 2 weeks of the
first dose of study treatment

- Any haematopoietic growth factors (e.g., filgrastim [G-CSF] or sargramostim
[GM-CSF]) within 7 days of the first dose of AZD2811 with or without azacitidine
or pegylated G-CSF (pegfilgrastim) or darbepoetin within 14 days of the first
dose of study treatment.

- Prescription or non-prescription drugs or other products known to be strong
inhibitors/inducers of CYP3A4 that cannot be discontinued prior to Day 1 of
dosing and withheld throughout the study until 2 weeks after the last dose of
study drug. Washout periods vary between 1 to 5 weeks depending on the
medication.

- Patients who have undergone allogeneic stem cell transplant within 12 months are
excluded. If allogeneic transplant was > 12 months ago, then they are not
excluded as long as they are off all immunosuppression and have no signs or
symptoms of active graft versus host disease.

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

2. With the exception of alopecia, any unresolved toxicities from prior therapy greater
than CTCAE Grade 1 at the time of starting study treatment.

3. Presence of, or history of leptomeningeal disease.

4. As judged by the Investigator, any evidence of: a) severe or uncontrolled systemic
diseases (e.g., severe hepatic impairment, interstitial lung disease [bilateral,
diffuse, parenchymal lung disease]); b) current unstable or uncompensated respiratory
or cardiac conditions; c) uncontrolled hypertension; d) history of, or active,
bleeding diatheses (e.g., haemophilia or von Willebrand disease); e) patients with
inflammatory bowel disease (e.g., Crohn's or colitis ulcerosa); uncontrolled active
systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing
signs/symptoms related to the infection and without improvement, despite appropriate
antibiotics or other treatment); or f) IV anti-infective treatment within 2 weeks
before first dose of study treatment.

5. Any of the following cardiac criteria:

- Congestive heart failure (CHF) per New York Heart Association (NYHA)
classification > Class II

- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy

- Unstable angina or new-onset angina

- QTcF interval > 450 ms (for male subjects) or >470 ms (for female subjects) on
screening ECG

6. Active non-infectious skin disease (including rash, dermatitis, or psoriasis, but
excluding stable plaque psoriasis from the definition of active disease). Patients
with a rash that is biopsy-proven leukaemia or with pressure ulcers are not excluded.
Patients with petechiae from thrombocytopenia or patients with drug related rashes
that are improving are not excluded.

7. Patients with a known hypersensitivity to azacitidine or mannitol (Combination
patients only).

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

9. Known history of infection with human immunodeficiency virus (HIV)

10. Serologic status reflecting active hepatitis B or C infection:

- Subjects who are anti-HBc positive and who are surface antigen negative will need
to have a negative PCR result before enrolment. Those who are hepatitis B surface
antigen positive or hepatitis B polymerase chain reaction (PCR) positive will be
excluded.

- Subjects who are hepatitis C antibody positive will need to have a negative PCR
result before enrolment. Those who are hepatitis C PCR positive will be excluded.