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

A Randomized, Multicenter, Open-label, Phase 2 Study Evaluating the Efficacy and Safety of Azacitidine Subcutaneous in Combination With Durvalumab (MEDI4736) in Previously Untreated Subjects With Higher-Risk Myelodysplastic Syndromes (MDS) or in Elderly (>= 65 Years) Acute Myeloid Leukemia (AML) Subjects Not Eligible for Hematopoietic Stem Cell Transplantation (HSCT)

The primary objective of this study is to evaluate the efficacy of subcutaneous azacitidine in combination with durvalumab as compared with subcutaneous azacitidine alone in adults with previously untreated, higher risk MDS who are not eligible for HSCT or in adults ≥ 65 years old with previously untreated AML who are not eligible for HSCT, with intermediate or poor cytogenetic risk.

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 potential may participate, providing they meet the following conditions:

   1. Have 2 negative pregnancy tests as verified by the Investigator prior to starting any investigational product (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 from heterosexual contact.
   2. Agree to practice true abstinence (which must be reviewed on a monthly basis and source documented) or agree to the use of a highly effective method of contraception use 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.
   4. Refrain from egg cell donation while taking durvalumab and for at least 90 days after the last dose of durvalumab.

4. Male subject must:

   1. Either practice true abstinence 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.

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:

    • 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 (erythropoietin-stimulating agents [ESAs], granulocyte colony-stimulating factor (G-CSF) and other red blood cell (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 monoclonal antibodies (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 (ESA with or without 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 white blood cell (WBC) count ≥ 15 × 10^9/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 WBC count ≥ 15 × 10^⁹/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