An Efficacy and Safety Study of Azacitidine Subcutaneous in Combination With Durvalumab (MEDI4736) in Previously Untreated Subjects With Higher-Risk Myelodysplastic Syndromes (MDS) or in Elderly Subjects With Acute Myeloid Leukemia (AML)

The enrollment period for this study is expected to last approximately 15 months. The
treatment and follow-up periods are expected to conclude approximately 12 months after the
last subject is randomized. Therefore, the total duration of the study is expected to be
approximately 27 months, from first subject enrolled until the last subject last visit.

Eligible subjects will be randomized to receive subcutaneous azacitidine alone or in
combination with durvalumab. The treatment phase will be conducted in 2 stages, with an
interim analysis for futility purpose, for each of the 2 study cohorts as outlined in Section
9. The primary analysis will follow completion of Stage 2 with additional analyses conducted
approximately 12 months after the last subject is enrolled, as described in Section 9.

Pharmacokinetic (PK) and immunogenicity sampling will be performed in subjects receiving the
combination therapy to assess durvalumab PK profile and development of antidrug antibodies.

Inclusion Criteria:

- For both cohorts:

1. Subject must understand and voluntarily sign an informed consent form (ICF) prior
to any study-related assessments/procedures being conducted.

2. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or
2.

3. Female subjects of childbearing potential1 may participate, providing they meet
the following conditions:

1. Have 2 negative pregnancy tests as verified by the Investigator prior to
starting any IP therapy: serum pregnancy test at screening and negative
serum or urine pregnancy test (Investigator's discretion) within 72 hours
prior to starting treatment with IP (Cycle 1, Day 1). They must agree to
ongoing pregnancy testing during the course of the study (before beginning
each subsequent cycle of treatment), and after the last dose of any IP. This
applies even if the subject practices complete abstinence[2] from
heterosexual contact.

2. Agree to practice true abstinence2 (which must be reviewed on a monthly
basis and source documented) or agree to the use of a highly effective
method of contraceptionuse from 28 days prior to starting durvalumab or
azacitidine, and must agree to continue using such precautions while taking
durvalumab or azacitidine (including dose interruptions) and up to 90 days
after the last dose of durvalumab or azacitidine. Cessation of contraception
after this point should be discussed with a responsible physician.

3. Agree to abstain from breastfeeding during study participation and for at
least 90 days after the last dose of IP.

c. Agree to abstain from breastfeeding during study participation and for at
least 90 days after the last dose of IP.

d. Refrain from egg cell donation while taking durvalumab and for at least 90
days after the last dose of durvalumab.

A female subject of childbearing potential (FCBP) is a female who:

1. has achieved menarche at some point

2. has not undergone a hysterectomy or bilateral oophorectomy or

3. has not been naturally postmenopausal (amenorrhea following cancer therapy does
not rule out childbearing potential) for at least 24 consecutive months (ie, has
had menses at any time in the preceding 24 consecutive months).

True abstinence is acceptable when this is in line with the preferred and usual
lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation,
symptothermal, postovulation methods) and withdrawal are not acceptable methods
of contraception.

4. Male subject must:

1. Either practice true abstinence3 from heterosexual contact (which must be
reviewed on a monthly basis) or agree to avoid fathering a child, to use highly
effective methods of contraception, male condom plus spermicide during sexual
contact with a pregnant female or a female of childbearing potential (even if he
has undergone a successful vasectomy) from starting dose of IP (Cycle 1 Day 1),
including dose interruptions through 90 days after receipt of the last dose of
durvalumab or azacitidine.

2. Refrain from semen or sperm donation while taking IP and for at least 90 days
after the last dose of IP.

True abstinence is acceptable when this is in line with the preferred and usual
lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation,
symptothermal, postovulation methods) and withdrawal are not acceptable methods
of contraception.

5. Understand and voluntarily sign a biomarker-specific component of the informed
consent form prior to any study-related procedures conducted.

6. Willing and able to adhere to the study visit schedule and other protocol
requirements.

MDS Cohort:

7. Age ≥ 18 years at the time of signing the informed consent form. 8. Central
confirmation of diagnosis of previously untreated primary or secondary
Myelodysplastic syndromes (MDS) as per World Health Organization (WHO)
classification. Results of central pathology review are required prior to
receiving the first dose of IP.

9. Central confirmation of the categorization of the MDS risk classification, as
per the Revised - International prognostic scoring system (IPSS-R) Intermediate
risk with >10% blasts or poor or very poor cytogenetics, or IPSS-R High or Very
High risk (Results of central pathology review required prior to receiving the
first dose of IP).

Acute myeloid leukemia (AML) Cohort:

10. Age ≥ 65 years at the time of signing the informed consent form (ICF). 11.
Central confirmation of diagnosis of one of the following untreated AML as per
WHO classification (Appendix I):

- Newly diagnosed, histologically confirmed de novo AML (bone marrow blasts ≥
20%), or

- AML secondary to prior MDS, or

- AML secondary to exposure to potentially leukemogenic therapies or agents
(eg, radiation therapy, alkylating agents, topoisomerase II inhibitors) with
the primary malignancy in remission for at least 2 years.

12. Central confirmation of intermediate or poor risk status, based on
Cytogenetics for Acute Myeloid Leukemia.

Exclusion Criteria:

- For both cohorts:

1. Prior hematopoietic stem cell transplant.

2. Considered eligible for hematopoietic stem cell transplant (allogeneic or
autologous) at the time of signing the ICF.

3. Prior exposure to azacitidine, decitabine or prior exposure to the
investigational oral formulation of decitabine, or other oral azacitidine
derivative.

4. Inaspirable bone marrow.

5. Use of any of the following within 28 days prior to the first dose of IP:

- Thrombopoiesis-stimulating agents (eg, romiplostim, eltrombopag,
Interleukin-11)

- Any hematopoietic growth factors (ESAs, Granulocyte colony-stimulating
factor (GCSF) and other RBC hematopoietic growth factors (eg, Interleukin-3)

- Any investigational agents within 28 days or 5 half-lives (whichever is
longer) of initiating study treatment

6. Prior history of malignancies, (except MDS for AML subjects), unless the subject
has been free of the disease for ≥ 2 years. However, subjects with the following
history/concurrent conditions are allowed:

- Basal or squamous cell carcinoma of the skin

- Carcinoma in situ of the cervix

- Carcinoma in situ of the breast

- Incidental histologic finding of prostate cancer (T1a or T1b using the
tumor, nodes, metastasis [Tumor, node, metastases (TNM)] clinical staging
system).

7. Pregnant or breast-feeding females or females who intend to become pregnant
during study participation.

8. Subject has active or prior documented autoimmune or inflammatory disorders
(including inflammatory bowel disease [eg, colitis, Crohn's disease],
diverticulitis with the exception of a prior episode that has resolved or
diverticulosis, celiac disease, irritable bowel disease [exclude only if active
within the last 6 months prior to signing the ICF], or other serious
gastrointestinal chronic conditions associated with diarrhea; systemic lupus
erythematosus; Wegener's syndrome [granulomatosis with polyangiitis]; myasthenia
gravis; Graves' disease; rheumatoid arthritis; hypophysitis, uveitis; etc) within
the past 3 years prior to the start of treatment. The following are exceptions to
this criterion:

- Subjects with vitiligo or alopecia;

- Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on
hormone replacement for ≥ 3 months prior to signing the ICF; or

- Subjects with psoriasis not requiring systemic treatment

9. Significant active cardiac disease within the previous 6 months prior to signing
the ICF, including:

- New York Heart Association (NYHA) Class III or IV congestive heart failure;

- Unstable angina or angina requiring surgical or medical intervention; and/or

- Significant cardiac arrhythmia

- Myocardial infarction

10. Uncontrolled intercurrent illness including, but not limited to, ongoing or
active systemic fungal, bacterial, or viral infection (defined as ongoing
signs/symptoms related to the infection without improvement despite appropriate
antibiotics or other treatment), uncontrolled hypertension, cardiac arrhythmia,
pneumonitis, interstitial lung disease, active peptic ulcer disease or gastritis
that would limit compliance with study requirement.

11. Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection, or
evidence of active Hepatitis B Virus (HBV) infection.

12. Known or suspected hypersensitivity to azacitidine, mannitol, or durvalumab, its
constituents, or to any other humanized monoclonal antibody.

13. Any significant medical condition, laboratory abnormality, or psychiatric illness
that would prevent the subject from participating in the study.

14. Any condition including the presence of laboratory abnormalities, which places
the subject at unacceptable risk if he/she were to participate in the study.

15. Prior anti- Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), Programmed
death-1 (PD-1), or Programmed death ligand-1 (PD-L1) or other immune checkpoint
mAb exposure.

16. Other investigational mAbs within 6 months prior to first dose of IP.

17. Current or prior use of immunosuppressive medication within 14 days prior to the
first dose of IP. The following are exceptions to this criterion:

- Intranasal, inhaled, topical, or local steroid injections (eg,
intra-articular injection)

- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or equivalent

- Steroids as premedication for hypersensitivity reactions (eg, computed
tomography [CT] scan premedication)

18. History of primary immunodeficiency.

19. Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP
(NOTE: Subjects, if enrolled, should not receive live vaccine during the study
and for 30 days after the last dose of durvalumab).

20. Unwilling or unable to complete subject reported outcome assessments without
assistance or with minimal assistance from trained site personnel and/or
caregiver.

21. Subjects who have had clinical evidence of central nervous system (CNS) or
pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia.

22. Presence of advanced malignant hepatic tumors.

23. Any of the following laboratory abnormalities:

- Serum aspartate aminotransferase (AST/SGOT) or alanine aminotransferase
(ALT/SGPT) > 2.5 × upper limit of normal (ULN)

- Serum total bilirubin > 1.5 × ULN. Higher levels are acceptable if these can
be attributed to active red blood cell precursor destruction within the bone
marrow (ie, ineffective erythropoiesis). Subjects are excluded if there is
evidence of autoimmune hemolytic anemia manifested as a corrected
reticulocyte count of > 2% with either a positive Coombs' test or over 50%
of indirect bilirubin

- Serum creatinine > 2.5 × ULN.

MDS Cohort:

24. Any previous cytotoxic, cytostatic, hormonal, biological or immunological
treatment for MDS (Erythropoietin-stimulating agent (ESA) with or without
granulocyte colony stimulating factor (G-CSF) are allowed under certain
conditions, see exclusion criterion # 5).

25. Any investigational therapy within 28 days prior to the first dose of IP.

26. Use of hydroxyurea within 2 weeks prior to obtaining the screening hematology
sample and prior to first dose of IP.

27. Absolute WBC count ≥ 15 × 109/L.

AML Cohort:

28. Previous cytotoxic, cytostatic, hormonal, biological or immunological treatment
(ESA with or without G-CSF and iron chelating therapy and hydroxyurea are allowed
under certain conditions, see exclusion criterion #5) or biologic treatment for
AML.

29. Any investigational therapy within 28 days prior to the first dose of IP.

30. Use of hydroxyurea within 2 weeks prior to obtaining the screening hematology
sample and prior to first dose of IP.

31. Prior use of targeted therapy agents (eg, FLT3 inhibitors, other kinase
inhibitors).

32. Suspected or proven acute promyelocytic leukemia (French-American-British (FAB)
M3) based on morphology, immunophenotype, molecular assay, or karyotype; AML
associated with t(9;22) karyotype, biphenotypic acute leukemia or AML with
previous hematologic disorder such as chronic myelogenous leukemia or
myeloproliferative neoplasms.

33. Acute myeloid leukemia associated with inv(16), t(8;21), t(16;16), t(15;17)
karyotypes or molecular evidence of such translocations if not associated with a
c-Kit mutation.

34. Absolute White blood cell (WBC) count ≥ 15 × 109/L (NOTE: Hydroxyurea is not
allowed to attain a WBC count ≤ 15 x 109/L).

35. Known history or presence of Sweet Syndrome at screening