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)

• Sponsor: Celgene (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02775903
• Collaborator: (none)
• Enrollment: 213
• Locations: 98
• Arms: 2
• Actual Duration (Months): 66.8
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Myeloid, Acute; Myelodysplastic Syndromes	Drug: Azacitidine; Biological: Durvalumab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 213 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: Jun 3, 2016
• Actual Primary Completion Date: Oct 31, 2018
• Actual Study Completion Date: Dec 27, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Azacitidine + Durvalumab Participants received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Drug: Azacitidine; Administered by subcutaneous injection on Days 1 to 7 of each 4-week treatment cycle.; Biological: Durvalumab; Administered by intravenous infusion on Day 1 of every 4-week treatment cycle.; Other Names: MEDI4736
Active Comparator: Azacitidine Alone Participants received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Drug: Azacitidine; Administered by subcutaneous injection on Days 1 to 7 of each 4-week treatment cycle.

Outcome Measures

Primary Outcome Measures

1. MDS Cohort: Overall Response Rate [Response was assessed following every 3 treatment cycles until treatment discontinuation; median duration of treatment was 239 days (AZA) and 215 days (DUR) in the AZA + DUR group and 210 days in the AZA alone group.]

   Overall response rate (ORR) is defined as the percentage of participants achieving a complete remission (CR), partial remission (PR), marrow complete remission (mCR), and/or hematological improvement (HI) based on International Working Group (IWG) 2006 response criteria for MDS and central review. CR: ≤ 5% myeloblasts in bone marrow (BM), and peripheral blood: hemoglobin ≥ 11 g/dL; platelets ≥ 100 × 10⁹/L; neutrophils ≥ 1.0 × 10⁹/L; blasts 0% PR: BM blasts decreased by ≥ 50% but still > 5%; peripheral blood as for CR mCR: BM ≤ 5% myeloblasts and decrease by ≥ 50% HI: Any of the following: •Hemoglobin increase by ≥ 1.5 g/dL or reduction of units of red blood cell (RBC) transfusions of at least 4 RBC transfusions/8 weeks compared with pretreatment •Absolute increase in platelets of ≥ 30 × 10⁹/L if pretreatment value > 20 × 10⁹/L or increase from < 20 × 10⁹/L to > 20 × 10⁹/L and by at least 100% •At least 100% increase in neutrophils and an absolute increase of > 0.5 × 10⁹/L

2. AML Cohort: Overall Response Rate [Response was assessed following every 3 treatment cycles until treatment discontinuation; median duration of treatment was 198 days (AZA) and 171 days (DUR) in the AZA + DUR group and 203 days in the AZA alone group.]

   Overall response rate for AML is defined as the percentage of participants achieving an overall response of morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) based on modified IWG 2003 response criteria for AML and central review. CR: The following conditions must be met: •Absolute neutrophil count (ANC) ≥ 1.0 x10⁹/L •Platelet count ≥ 100 x10⁹/L •The bone marrow should contain less than 5% blast cells; •Auer rods should not be detectable; •No platelet, or whole blood transfusions for 7days prior to the date of the hematology assessment. CRi: Defined as a morphologic complete remission but the ANC count may be < 1.0 x10⁹/L and/or the platelet count may be < 100 x10⁹/L.

Secondary Outcome Measures

1. MDS Cohort: Kaplan Meier Estimate of Time to First Response [Response was assessed following every 3 treatment cycles until treatment discontinuation; median duration of treatment was 239 days (AZA) and 215 days (DUR) in the AZA + DUR group and 210 days in the AZA alone group.]

   Time to first response is defined as the time from randomization to the earliest date any response (CR, PR, mCR, or HI) was observed, according to IWG 2006 response criteria for MDS and central review. Participants who did not achieve any defined response were censored at the date of last adequate response assessment, disease progression, or death, whichever occurred first.

2. MDS Cohort: Kaplan Meier Estimate of Relapse-free Survival [From randomization to the final analysis data cut-off date of 31 October 2018; maximum follow-up for survival was approximately 2 years.]

   Relapse-free survival is defined as the time from the date of first documented response (CR or PR) to the date of disease relapse or death from any cause, whichever occurred first according to IWG 2006 response criteria for MDS and central review. Participants who were still alive and progression-free were censored at the date of their last response assessment. Participants who received a subsequent therapy before the date of disease relapse or death were censored at the time of subsequent therapy. Relapse after CR or PR is defined as at least one of the following: •Return to pretreatment bone marrow blast % •Decrement of ≥ 50% from maximum remission/response levels in granulocytes or platelets •Reduction in hemoglobin concentration by ≥ 1.5 g/dL or transfusion dependence

3. MDS Cohort: Percentage of Participants Who Achieved a Cytogenetic Response [Response was assessed following every 3 treatment cycles until treatment discontinuation; median duration on treatment was 239 days (AZA) and 215 days (DUR) in the AZA + DUR group and 210 days in the AZA alone group.]

   Cytogenetic response is defined as the percentage of participants who achieved a complete cytogenetic response or partial cytogenetic response according to IWG 2006 response criteria and central review. Complete cytogenetic response: Disappearance of the baseline chromosomal abnormality without appearance of new abnormalities. Partial cytogenetic response: At least 50% reduction of the chromosomal abnormality.

4. MDS Cohort: Kaplan-Meier Estimate of Progression-free Survival (PFS) [From randomization to the final analysis data cut-off date of 31 October 2018; maximum follow-up for survival was approximately 2 years.]

   Progression-free survival is defined as the time from randomization to the first documented progressive disease (PD), relapse, or death due to any cause during or after the treatment period, whichever occurred first, according to IWG 2006 response criteria for MDS and central review. Participants who were still alive and progression-free were censored at the date of their last response assessment. Progressive disease is defined as follows: - an increase in BM blasts relative to nadir: •If nadir less than 5% blasts: ≥ 50% increase in blasts to > 5% blasts •If nadir 5% - 10% blasts: ≥ 50% increase in blasts to > 10% blasts •If nadir 10% - 20% blasts: ≥ 50% increase in blasts to > 20% blasts •If nadir 20% - 30% blasts: ≥ 50% increase in blasts to > 30% blasts And any of the following: •At least 50% decrement from maximum remission/response levels in granulocytes or platelets •Reduction in Hgb concentration by ≥ 2 g/dL •Transfusion dependence

5. MDS Cohort: Kaplan-Meier Estimate of Duration of Response [From randomization to the final analysis data cut-off date of 31 October 2018; median duration of treatment was 239 days (AZA) and 215 days (DUR) in the AZA + DUR group and 210 days in the AZA alone group.]

   Duration of response is defined as the time from when the first overall response (CR, mCR, PR, or HI) was observed until relapse, PD, or death, as defined by the IWG 2006 response criteria and central review. If no relapse, PD, or death was observed, the duration of response was censored at the last response assessment date that the participant was known to be progression-free.

6. MDS Cohort: Kaplan-Meier Estimate of Time to AML Transformation [From randomization to the final analysis data cut-off date of 31 October 2018; maximum follow-up for survival was approximately 2 years.]

   Participants were monitored for transformation to AML until death, lost to follow-up, withdrawal of consent for further data collection, or the end of the trial. Time to transformation to AML is defined as the time from the date of randomization until the date the participant had documented transformation to AML (defined as at least 30% of myeloblasts in the bone marrow). Participants with no transformation to AML were censored at the date of their last disease assessment.

7. MDS Cohort: Percentage of Participants With Disease Transformation to AML [From randomization to the final analysis data cut-off date of 31 October 2018; maximum follow-up for survival was approximately 2 years.]

   Disease transformation to AML is defined as at least 30% myeloblasts in the bone marrow. Participants were monitored for transformation to AML until death, lost to follow-up, withdrawal of consent for further data collection, or the end of the trial.

8. AML Cohort: Kaplan Meier Estimate of Time to First Response [Response was assessed following every 3 treatment cycles until treatment discontinuation; median duration of treatment was 198 days (AZA) and 171 days (DUR) in the AZA + DUR group and 203 days in the AZA alone group.]

   Time to first response is defined as the time between the date of randomization and the earliest date any response (CR or CRi) was observed based on modified IWG 2003 response criteria for AML and central review. Participants who did not achieve any defined response were censored at the date of last adequate response assessment, disease progression, or death, whichever occurred first.

9. AML Cohort: Kaplan Meier Estimate of Relapse-free Survival [From randomization to the final analysis data cut-off date of 31 October 2018; maximum follow-up for survival was approximately 2 years.]

   Relapse-free survival is defined as time from the date of first documented response (CR and CRi) to the date of disease relapse or death from any cause, whichever occurred first based on modified IWG 2003 response criteria for AML and central review. Participants who were still alive and progression-free were censored at the date of their last response assessment. Participants who received a subsequent therapy before the date of disease relapse or death were censored at the time of subsequent therapy.

10. AML Cohort: Percentage of Participants Who Achieved a Complete Cytogenetic Response [Response was assessed following every 3 treatment cycles until treatment discontinuation; median duration of treatment was 198 days (AZA) and 171 days (DUR) in the AZA + DUR group and 203 days in the AZA alone group.]

    Complete cytogenetic response (CyCR) based on modified IWG 2003 response criteria is defined as morphologic complete remission with a reversion to a normal karyotype. The following conditions must be met: • Absolute neutrophil count (ANC) ≥ 1.0 x10⁹/L • Platelet count ≥ 100 x10⁹/L • The bone marrow should contain less than 5% blast cells; • Auer rods should not be detectable; • No platelet, or whole blood transfusions for 7days prior to the date of the hematology assessment. AND • Reversion to normal karyotype at time of CR (based on ≥ 10 metaphases).

11. AML Cohort: Percentage of Participants With Hematologic Improvement [Response was assessed following every 3 treatment cycles until treatment discontinuation; median duration of treatment was 198 days (AZA) and 171 days (DUR) in the AZA + DUR group and 203 days in the AZA alone group.]

    Hematological improvement was defined as participants with a erythroid response (HI-E), platelet response (HI-P) or neutrophil response (HI-NE) for at least 8 weeks, according to the IWG 2006 response criteria: Hi-E (in participants with pretreatment hemoglobin < 11 g/dL or red blood cell (RBC)-transfusion dependent): Hemoglobin increase of ≥ 1.5 g/dL, or reduction in units of RBC transfusions of at least 4 RBC transfusions/8 weeks compared with the 8 weeks prior to pretreatment. HI-P (in participants with pretreatment platelet count < 100 × 10⁹/L): Absolute increase in platelets of ≥ 30 × 10⁹/L if pretreatment value > 20 × 10⁹/L or increase from < 20 × 10⁹/L to > 20 × 10⁹/L and by at least 100%. HI-N (in participants with pretreatment neutrophils < 1.0 × 10⁹/L): At least 100% increase in neutrophils and an absolute increase of > 0.5 × 10⁹/L.

12. AML Cohort: Kaplan-Meier Estimate of Duration of Response [Response was assessed following every 3 treatment cycles until treatment discontinuation; median duration of treatment was 198 days (AZA) and 171 days (DUR) in the AZA + DUR group and 203 days in the AZA alone group.]

    Duration of response is defined as the time from the first response (CR or CRi) was observed until relapse, PD, or death based on the IWG 2003 response criteria and central review. If no relapse, PD, or death was observed, the duration of response was censored at the last response assessment date that the participant was known to be progression-free.

13. Number of Participants With Treatment-emergent Adverse Events (TEAEs) [MDS cohort: up to 776 days in the AZA + DUR arm and 679 days in the AZA alone arm; AML cohort: up to 840 days in the AZA + DUR arm and 656 days in the AZA alone arm.]

    Treatment emergent adverse events are adverse events (AEs) that occurred or worsened on or after the first dose of study drug (durvalumab or azacitidine) and within 90 days after last dose of durvalumab or 28 days after last dose of azacitidine. A treatment-related TEAE is a TEAE where the causal relationship was assessed by the investigator as "Suspected". The intensity of AEs was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03: Grade 1 (Mild): asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 (Moderate): minimal, local or noninvasive intervention indicated; limiting age-appropriate activities of daily living. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death due to AE.

14. Kaplan-Meier Estimate of Overall Survival [From randomization to the final analysis data cut-off date of 31 October 2018; maximum follow-up for survival was approximately 2 years.]

    Overall survival is defined as the time between randomization and death/censored date. Participants who were alive at the time of the clinical data cut-off were censored at the last known alive date.

15. One-year Survival [12 months]

    One-year survival is defined as the probability of survival at 1 year from randomization and is represented by the Kaplan-Meier estimate of the percentage of participants alive after 1 year.

16. Durvalumab Serum Concentration [Cycle 1 Day 1 end of infusion (EOI), Cycle 2 Day 1 pre-infusion, Cycle 4 Day 1 pre-infusion and EOI, and Cycle 6 Day 1 pre-infusion]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

4. 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.

5. 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.

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

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

8. Male subject must:

9. 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.

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

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

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

MDS Cohort:

1. Age ≥ 18 years at the time of signing the informed consent form.

2. 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.

3. 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:

1. Age ≥ 65 years at the time of signing the informed consent form (ICF).

2. 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.

1. 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

1. 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).

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

2. 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

1. 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

1. 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.

2. Known human immunodeficiency virus (HIV) or hepatitis C (HCV) infection, or evidence of active hepatitis B virus (HBV) infection.

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

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

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

6. 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.

7. Other investigational monoclonal antibodies (mAbs) within 6 months prior to first dose of IP.

8. 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)

1. History of primary immunodeficiency.

2. 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).

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

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

5. Presence of advanced malignant hepatic tumors.

6. 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:

1. 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).

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

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

4. Absolute white blood cell (WBC) count ≥ 15 × 10^9/L.

AML Cohort:

1. 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.

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

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

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

5. 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.

6. 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.

7. Absolute WBC count ≥ 15 × 10^⁹/L (NOTE: Hydroxyurea is not allowed to attain a WBC count ≤ 15 x 10⁹/L).

8. Known history or presence of Sweet Syndrome at screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale Cancer Center	New Haven	Connecticut	United States	06520
2	Georgetown University Hospital	Washington	District of Columbia	United States	20007
3	University of Florida	Gainesville	Florida	United States	32610
4	Moffitt Cancer Center	Tampa	Florida	United States	33612
5	University of Chicago	Chicago	Illinois	United States	60637
6	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
7	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
8	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
9	Duke University Medical Center	Durham	North Carolina	United States	27705
10	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
11	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37203
12	University of Texas- MD Anderson	Houston	Texas	United States	77230
13	Medizinische Universitat Graz	Graz		Austria	8036
14	Medizinische Universitat Innsbruck	Innsbruck		Austria	6020
15	Elisabethinen Hospital Linz	Linz		Austria	4020
16	Salzburger Landkliniken St. Johanns-Spital	Salzburg		Austria	5020
17	AKH Wien	Wein		Austria	1090
18	Hanusch Krankenhaus der Stadt Wien	Wien		Austria	1140
19	Cliniques Universitaires St-Luc	Brussels		Belgium	1200
20	Grand Hopital de Charleroi	Charleroi		Belgium	6000
21	Local Institution - 202	Gent		Belgium	9000
22	UH Gent	Gent		Belgium	9000
23	UH Gasthuisberg	Leuven		Belgium	3000
24	Cliniques Universitaires UCL de Mont-Godine	Yvoir		Belgium	5530
25	University of Alberta	Edmonton	Alberta	Canada	T6g2b7
26	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
27	Saint John Regional Hospital	Saint John	New Brunswick	Canada	E2L 4L2
28	Ottawa General Hospital	Ottawa	Ontario	Canada	K1H 8L6
29	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
30	CHUM - Notre Dame	Montreal	Quebec	Canada	H2L 4M1
31	Centre Hospitalier Universitaire d' Angers	Angers		France	67091
32	Hopital Avicenne	Bobigny Cedex		France	93009
33	Hopital Henri Mondor	Creteil		France	94010
34	Centre Hospitalier Universitaire de Grenoble Hopital Albert Michallon	La Tronche		France	38700
35	Centre Leon Berard	Lyon		France	69008
36	CHRU de Nantes - Hotel Dieu	Nantes		France	44093
37	Hopital Saint Louis	Paris		France	75010
38	Local Institution - 251	Paris		France	75010
39	CHU Bordeaux	Pessac		France	33604
40	Local Institution - 254	Pessac		France	33604
41	Centre Hospitalier Lyon Sud	Pierre-Bénite Cedex		France	69495
42	IUCT Oncopole	Toulouse		France	31059 Cedex 9
43	Local Institution - 604	Dresden		Germany	01307
44	Universitatsklinikum Carl Gustav Carus	Dresden		Germany	01307
45	Local Institution - 603	Dusseldorf		Germany	40479
46	Marien Hospital	Dusseldorf		Germany	40479
47	Universitatsklinikum Essen	Essen		Germany	45122
48	Klinikum der Johann Wolfgang Goethe Universitat	Frankfurt am Main		Germany	60590
49	Universitatsklinikum Freiburg	Freiburg		Germany	79106
50	Medizinische Hochschule HannoverZentrum Innere Medizin	Hannover		Germany	30625
51	Universitatsklinikum Leipzig	Leipzig		Germany	04103
52	Klinikum der LMU Campus Grosshadern	Munchen		Germany	1307
53	Klinikum rechts der Isar der TU Munchen	Munchen		Germany	81675
54	Universitatsklinikum Ulm	Ulm		Germany	89081
55	AO Spedali Civili di Brescia	Brecia		Italy	25123
56	Azienda Ospedaliero-Universitaria Careggi	Firenze		Italy	50134
57	Ospedale Niguarda Milano	Milano		Italy	20162
58	Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello	Palermo		Italy	33100
59	I.R.C.C.S. Policlinico San Matteo - Universita di Pavia	Pavia		Italy	27100
60	Local Institution - 302	Pavia		Italy	27100
61	Azienda Ospedaliera Bianchi-Melacrino-Morelli	Roma		Italy	133
62	Local Institution - 303	Roma		Italy	133
63	Policlinico Agostino Gemelli - Istituto di Ematologia	Roma		Italy	89100
64	Azienda Ospedaliera Universitaria Policlinico Tor Vergata	Rome		Italy	133
65	Local Institution - 304	Rome		Italy	133
66	Azienda Ospedaliero-Universitaria Santa Maria della Misericordia die Udine	Udine		Italy	30174
67	Universita degli Studi dell'Insubria - Ospedale di Circolo e Fondazione Macchi - Varese	Varese		Italy	21100
68	VU University Medical Center	Amsterdam		Netherlands	1081 HV
69	Oddzial Hematologii Onkologicznej Szpital Specjalistyczny w Brzozowie Podkarpacki Osrodek Onkologicz	Brzozow		Poland	36-200
70	Katedra i Klinika Hematologii i Transplantologii Uniwersyteckie Centrum Kliniczne	Gdansk		Poland	80-211
71	Samodzielny Publiczny Szpital Kliniczny nr 1 Klinika Hematoonkologii i Transplantacji Szpiku	Lubin		Poland	20-081
72	Oddzial Hematologii Samodzielny Publiczny Zaklad Opieki Zdrowotnej MSW	Olsztyn		Poland	10-228
73	Klinika Hematologii Nowotworow Krwi i Transplantacji Szpiku	Wroclaw		Poland	50-367
74	Hospitais da Universidade de Coimbra	Coimbra		Portugal	3000-076
75	Instituto Portugues de Oncologia de Lisboa Francisco Gentil EPE	Lisbon		Portugal	1099-023
76	Ipo Instituto Portugues De Oncologia Porto	Porto		Portugal	4200-072
77	Local Institution - 502	Porto		Portugal	4200-072
78	Hospital de Sao Joao	Porto		Portugal	4200
79	Hospital Universitario Vall D hebron	Barcelona		Spain	28040
80	Hospital Clinic I Provincial de Barcelona	Barcelona		Spain	8036
81	Complejo Hospitalario San Pedro de Alcantara	Caceres		Spain	10003
82	Hospital Universitario La Princesa	Madrid		Spain	28006
83	Hospital Gregorio Maranon	Madrid		Spain	37007
84	Hospital Universitario Virgen de la Victoria	Malaga		Spain	29010
85	Hospital Son Llatzer	Palma de Mallorca		Spain	7198
86	Hospital Universitario de Salamanca	Salamanca		Spain	37007
87	Hospital Virgen del Rocio	Sevilla		Spain	41013
88	Hospital Universitario La Fe	Valencia		Spain	46009
89	Hospital Clinico Universitario de Valencia	Valencia		Spain	46010
90	University Hospital Birmingham	Birmingham		United Kingdom	B15 2TH
91	St James University Hospital	Leeds		United Kingdom	LS1 3EX
92	University College London Hospital	London Bloomsbury		United Kingdom	WC1E 6AU
93	St Bartholomews Hospital	London		United Kingdom	EC1 7BE
94	Kings College Hospital	London		United Kingdom	SE5 9RS
95	The Christie NHS Foundation Trust	Manchester		United Kingdom	M20 4BX
96	John Radcliffe Hospital	Oxford		United Kingdom	OX3 9DU
97	Local Institution - 453	Oxford		United Kingdom	OX3 9DU
98	The Royal Marsden NHS Foundation Trust	Sutton		United Kingdom	SM2 5PT

Sponsors and Collaborators

• Celgene

Investigators

• Study Director: CL Beach, Pharm D, Celgene Corporation

Study Documents (Full-Text)

• Study Protocol - Mar 5, 2019
• Statistical Analysis Plan - Oct 23, 2017

More Information

Publications

None provided.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT02775903
• Other Study ID Numbers: MEDI4736-MDS-001
• First Posted: May 18, 2016
• Last Update Posted: Aug 22, 2022
• Last Verified: Aug 1, 2022

• Keywords provided by Celgene: MEDI4736; Durvalumab; Myelodysplastic Syndromes; Acute Myeloid Leukemia; Hematopoietic Stem Cell Transplantation; Azacitidine; Safety; Efficacy; PD-L1
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Syndrome; Azacitidine; Durvalumab

Study Results

Participant Flow

Recruitment Details	This study consisted of 2 cohorts: • Adults with previously untreated intermediate, high or very high risk myelodysplastic syndromes (MDS) not eligible for hematopoietic stem cell transplantation (HSCT). • Adults with previously untreated acute myeloid leukemia (AML) ≥ 65 years and not eligible for HSCT with intermediate or poor cytogenetic risk.
Pre-assignment Detail	Within each cohort participants were randomized in a 1:1 ratio to receive either azacitidine plus durvalumab or azacitidine alone. Randomization was stratified according to cytogenetic risk: • Very good, good and intermediate versus poor and very poor for MDS • Intermediate versus poor for AML Results are up to the data cutoff of 31 October 2018.

Arm/Group Title	MDS: Azacitidine + Durvalumab	MDS: Azacitidine Alone	AML: Azacitidine + Durvalumab	AML: Azacitidine Alone
Arm/Group Description	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Period Title: Overall Study
STARTED	42	42	64	65
Received Study Treatment	38	41	64	62
COMPLETED	0	1	0	0
NOT COMPLETED	42	41	64	65

Baseline Characteristics

Arm/Group Title	MDS: Azacitidine + Durvalumab	MDS: Azacitidine Alone	AML: Azacitidine + Durvalumab	AML: Azacitidine Alone	Total
Arm/Group Description	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Total of all reporting groups
Overall Participants	42	42	64	65	213
Age (years) [Mean (Standard Deviation) ]
MDS	72.5 (6.53)	73.2 (8.83)	72.8 (7.72)
AML	76.2 (5.97)	75.3 (5.36)	75.8 (5.67)
Age, Customized (Count of Participants)
< 65 years	2 4.8%	10 23.8%	12 18.8%
≥ 65 to < 75 years	21 50%	11 26.2%	32 50%
≥ 75 years	19 45.2%	21 50%	40 62.5%
< 65 years	0 0%	0 0%	0 0%
≥ 65 to < 75 years	24 57.1%	28 66.7%	52 81.3%
≥ 75 years	40 95.2%	37 88.1%	77 120.3%
Sex: Female, Male (Count of Participants)
Female	14 33.3%	12 28.6%	26 40.6%
Male	28 66.7%	30 71.4%	58 90.6%
Female	24 57.1%	34 81%	58 90.6%
Male	40 95.2%	31 73.8%	71 110.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 11.9%	2 4.8%	7 10.9%
Not Hispanic or Latino	30 71.4%	33 78.6%	63 98.4%
Unknown or Not Reported	7 16.7%	7 16.7%	14 21.9%
Hispanic or Latino	6 14.3%	3 7.1%	9 14.1%
Not Hispanic or Latino	39 92.9%	41 97.6%	80 125%
Unknown or Not Reported	19 45.2%	21 50%	40 62.5%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 4.8%	1 2.4%	3 4.7%
Black or African American	1 2.4%	0 0%	1 1.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
White	30 71.4%	33 78.6%	63 98.4%
Not Collected or Reported	7 16.7%	5 11.9%	12 18.8%
Other	2 4.8%	3 7.1%	5 7.8%
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Black or African American	0 0%	1 2.4%	1 1.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
White	45 107.1%	42 100%	87 135.9%
Not Collected or Reported	18 42.9%	21 50%	39 60.9%
Other	1 2.4%	1 2.4%	2 3.1%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
0 - Fully active	17 40.5%	18 42.9%	35 54.7%
1 - Restricted but ambulatory	20 47.6%	20 47.6%	40 62.5%
2 - Ambulatory but unable to work	3 7.1%	4 9.5%	7 10.9%
3 - Limited self-care	0 0%	0 0%	0 0%
4 - Completely Disabled	0 0%	0 0%	0 0%
Missing	2 4.8%	0 0%	2 3.1%
0 - Fully active	19 45.2%	26 61.9%	45 70.3%
1 - Restricted but ambulatory	40 95.2%	32 76.2%	72 112.5%
2 - Ambulatory but unable to work	5 11.9%	7 16.7%	12 18.8%
3 - Limited self-care	0 0%	0 0%	0 0%
4 - Completely Disabled	0 0%	0 0%	0 0%
Missing	0 0%	0 0%	0 0%
Revised International Prognostic Scoring System (IPSS-R) Cytogenetic Risk Groups (MDS Cohort) (Count of Participants)
Very good	1 2.4%	1 2.4%	2 3.1%
Good	10 23.8%	10 23.8%	20 31.3%
Intermediate	9 21.4%	8 19%	17 26.6%
Poor	8 19%	9 21.4%	17 26.6%
Very Poor	14 33.3%	14 33.3%	28 43.8%
Cytogenetic Risk Classifications (AML Cohort) (Count of Participants)
Better risk	0 0%	0 0%	0 0%
Intermediate risk	25 59.5%	26 61.9%	51 79.7%
Poor risk	16 38.1%	16 38.1%	32 50%
Missing	23 54.8%	23 54.8%	46 71.9%

Outcome Measures

1. Primary Outcome

Title	MDS Cohort: Overall Response Rate
Description	Overall response rate (ORR) is defined as the percentage of participants achieving a complete remission (CR), partial remission (PR), marrow complete remission (mCR), and/or hematological improvement (HI) based on International Working Group (IWG) 2006 response criteria for MDS and central review. CR: ≤ 5% myeloblasts in bone marrow (BM), and peripheral blood: hemoglobin ≥ 11 g/dL; platelets ≥ 100 × 10⁹/L; neutrophils ≥ 1.0 × 10⁹/L; blasts 0% PR: BM blasts decreased by ≥ 50% but still > 5%; peripheral blood as for CR mCR: BM ≤ 5% myeloblasts and decrease by ≥ 50% HI: Any of the following: •Hemoglobin increase by ≥ 1.5 g/dL or reduction of units of red blood cell (RBC) transfusions of at least 4 RBC transfusions/8 weeks compared with pretreatment •Absolute increase in platelets of ≥ 30 × 10⁹/L if pretreatment value > 20 × 10⁹/L or increase from < 20 × 10⁹/L to > 20 × 10⁹/L and by at least 100% •At least 100% increase in neutrophils and an absolute increase of > 0.5 × 10⁹/L
Time Frame	Response was assessed following every 3 treatment cycles until treatment discontinuation; median duration of treatment was 239 days (AZA) and 215 days (DUR) in the AZA + DUR group and 210 days in the AZA alone group.

Outcome Measure Data

Analysis Population Description

All randomized participants in the MDS cohort; participants who discontinued before 6 cycles of treatment without achieving overall response were counted as non-responders.

Arm/Group Title	MDS: Azacitidine + Durvalumab	MDS: Azacitidine Alone
Arm/Group Description	Participants with MDS received 75 mg/m² subcutaneous azacitidine (AZA) for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab (DUR) on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Measure Participants	42	42
Number (95% Confidence Interval) [percentage of participants]	61.9 147.4%	47.6 113.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MDS: Azacitidine + Durvalumab, MDS: Azacitidine Alone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1838
	Comments
	Method	Wald asymptotic two-sided test
	Comments

2. Primary Outcome

Title	AML Cohort: Overall Response Rate
Description	Overall response rate for AML is defined as the percentage of participants achieving an overall response of morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) based on modified IWG 2003 response criteria for AML and central review. CR: The following conditions must be met: •Absolute neutrophil count (ANC) ≥ 1.0 x10⁹/L •Platelet count ≥ 100 x10⁹/L •The bone marrow should contain less than 5% blast cells; •Auer rods should not be detectable; •No platelet, or whole blood transfusions for 7days prior to the date of the hematology assessment. CRi: Defined as a morphologic complete remission but the ANC count may be < 1.0 x10⁹/L and/or the platelet count may be < 100 x10⁹/L.
Time Frame	Response was assessed following every 3 treatment cycles until treatment discontinuation; median duration of treatment was 198 days (AZA) and 171 days (DUR) in the AZA + DUR group and 203 days in the AZA alone group.

Outcome Measure Data

Analysis Population Description

All randomized participants in the AML cohort; participants who discontinued before 6 cycles of treatment without achieving overall response were counted as non-responders.

Arm/Group Title	AML: Azacitidine + Durvalumab	AML: Azacitidine Alone
Arm/Group Description	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Measure Participants	64	65
Number (95% Confidence Interval) [percentage of participants]	31.3 74.5%	35.4 84.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MDS: Azacitidine + Durvalumab, MDS: Azacitidine Alone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6180
	Comments
	Method	Wald asymptotic two-sided test
	Comments

3. Secondary Outcome

Title	MDS Cohort: Kaplan Meier Estimate of Time to First Response
Description	Time to first response is defined as the time from randomization to the earliest date any response (CR, PR, mCR, or HI) was observed, according to IWG 2006 response criteria for MDS and central review. Participants who did not achieve any defined response were censored at the date of last adequate response assessment, disease progression, or death, whichever occurred first.
Time Frame	Response was assessed following every 3 treatment cycles until treatment discontinuation; median duration of treatment was 239 days (AZA) and 215 days (DUR) in the AZA + DUR group and 210 days in the AZA alone group.

Outcome Measure Data

Analysis Population Description

All participants randomized in the MDS cohort

Arm/Group Title	MDS: Azacitidine + Durvalumab	MDS: Azacitidine Alone
Arm/Group Description	Participants with MDS received 75 mg/m² subcutaneous azacitidine (AZA) for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab (DUR) on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Measure Participants	42	42
Median (95% Confidence Interval) [weeks]	14.3	18.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MDS: Azacitidine + Durvalumab, MDS: Azacitidine Alone
	Comments
	Type of Statistical Test	Other
	Comments	P-values were not part of the formal testing.
Statistical Test of Hypothesis	p-Value	0.7016
	Comments
	Method	Log Rank
	Comments	Log-rank test stratified according to the cytogenetic risk at time of randomization (very good, good and intermediate vs poor and very poor)

4. Secondary Outcome

Title	MDS Cohort: Kaplan Meier Estimate of Relapse-free Survival
Description	Relapse-free survival is defined as the time from the date of first documented response (CR or PR) to the date of disease relapse or death from any cause, whichever occurred first according to IWG 2006 response criteria for MDS and central review. Participants who were still alive and progression-free were censored at the date of their last response assessment. Participants who received a subsequent therapy before the date of disease relapse or death were censored at the time of subsequent therapy. Relapse after CR or PR is defined as at least one of the following: •Return to pretreatment bone marrow blast % •Decrement of ≥ 50% from maximum remission/response levels in granulocytes or platelets •Reduction in hemoglobin concentration by ≥ 1.5 g/dL or transfusion dependence
Time Frame	From randomization to the final analysis data cut-off date of 31 October 2018; maximum follow-up for survival was approximately 2 years.

Outcome Measure Data

Analysis Population Description

Participants randomized in the MDS cohort who had a CR or PR

Arm/Group Title	MDS: Azacitidine + Durvalumab	MDS: Azacitidine Alone
Arm/Group Description	Participants with MDS received 75 mg/m² subcutaneous azacitidine (AZA) for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab (DUR) on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Measure Participants	3	4
Median (95% Confidence Interval) [months]	3.7	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MDS: Azacitidine + Durvalumab, MDS: Azacitidine Alone
	Comments
	Type of Statistical Test	Other
	Comments	P-values were not part of the formal testing.
Statistical Test of Hypothesis	p-Value	0.6076
	Comments
	Method	Log Rank
	Comments	Log-rank test stratified according to the cytogenetic risk at time of randomization (very good, good and intermediate vs poor and very poor).

5. Secondary Outcome

Title	MDS Cohort: Percentage of Participants Who Achieved a Cytogenetic Response
Description	Cytogenetic response is defined as the percentage of participants who achieved a complete cytogenetic response or partial cytogenetic response according to IWG 2006 response criteria and central review. Complete cytogenetic response: Disappearance of the baseline chromosomal abnormality without appearance of new abnormalities. Partial cytogenetic response: At least 50% reduction of the chromosomal abnormality.
Time Frame	Response was assessed following every 3 treatment cycles until treatment discontinuation; median duration on treatment was 239 days (AZA) and 215 days (DUR) in the AZA + DUR group and 210 days in the AZA alone group.

Outcome Measure Data

Analysis Population Description

Participants randomized in the MDS cohort evaluable for cytogenetic response (ie, participants with baseline cytogenetic abnormalities).

Arm/Group Title	MDS: Azacitidine + Durvalumab	MDS: Azacitidine Alone
Arm/Group Description	Participants with MDS received 75 mg/m² subcutaneous azacitidine (AZA) for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab (DUR) on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Measure Participants	21	23
Number (95% Confidence Interval) [percentage of participants]	47.6 113.3%	34.8 82.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MDS: Azacitidine + Durvalumab, MDS: Azacitidine Alone
	Comments
	Type of Statistical Test	Other
	Comments	P-values were not part of the formal testing.
Statistical Test of Hypothesis	p-Value	0.3840
	Comments
	Method	Wald asymptotic two-sided test
	Comments

6. Secondary Outcome

Title	MDS Cohort: Kaplan-Meier Estimate of Progression-free Survival (PFS)
Description	Progression-free survival is defined as the time from randomization to the first documented progressive disease (PD), relapse, or death due to any cause during or after the treatment period, whichever occurred first, according to IWG 2006 response criteria for MDS and central review. Participants who were still alive and progression-free were censored at the date of their last response assessment. Progressive disease is defined as follows: - an increase in BM blasts relative to nadir: •If nadir less than 5% blasts: ≥ 50% increase in blasts to > 5% blasts •If nadir 5% - 10% blasts: ≥ 50% increase in blasts to > 10% blasts •If nadir 10% - 20% blasts: ≥ 50% increase in blasts to > 20% blasts •If nadir 20% - 30% blasts: ≥ 50% increase in blasts to > 30% blasts And any of the following: •At least 50% decrement from maximum remission/response levels in granulocytes or platelets •Reduction in Hgb concentration by ≥ 2 g/dL •Transfusion dependence
Time Frame	From randomization to the final analysis data cut-off date of 31 October 2018; maximum follow-up for survival was approximately 2 years.

Outcome Measure Data

Analysis Population Description

Participants randomized in the MDS cohort (PFS was a pre-specified secondary outcome measure in the MDS cohort only).

Arm/Group Title	MDS: Azacitidine + Durvalumab	MDS: Azacitidine Alone
Arm/Group Description	Participants with MDS received 75 mg/m² subcutaneous azacitidine (AZA) for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab (DUR) on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Measure Participants	42	42
Median (95% Confidence Interval) [months]	8.7	8.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MDS: Azacitidine + Durvalumab, MDS: Azacitidine Alone
	Comments
	Type of Statistical Test	Other
	Comments	P-values were not part of the formal testing.
Statistical Test of Hypothesis	p-Value	0.9330
	Comments
	Method	Log Rank
	Comments	Log-rank test stratified according to the cytogenetic risk at time of randomization (very good, good and intermediate vs poor and very poor).

7. Secondary Outcome

Title	MDS Cohort: Kaplan-Meier Estimate of Duration of Response
Description	Duration of response is defined as the time from when the first overall response (CR, mCR, PR, or HI) was observed until relapse, PD, or death, as defined by the IWG 2006 response criteria and central review. If no relapse, PD, or death was observed, the duration of response was censored at the last response assessment date that the participant was known to be progression-free.
Time Frame	From randomization to the final analysis data cut-off date of 31 October 2018; median duration of treatment was 239 days (AZA) and 215 days (DUR) in the AZA + DUR group and 210 days in the AZA alone group.

Outcome Measure Data

Analysis Population Description

Participants randomized in the MDS cohort with an overall response (CR, mCR, PR, or HI)

Arm/Group Title	MDS: Azacitidine + Durvalumab	MDS: Azacitidine Alone
Arm/Group Description	Participants with MDS received 75 mg/m² subcutaneous azacitidine (AZA) for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab (DUR) on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Measure Participants	26	20
Median (95% Confidence Interval) [weeks]	33.9	39.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MDS: Azacitidine + Durvalumab, MDS: Azacitidine Alone
	Comments
	Type of Statistical Test	Other
	Comments	P-values were not part of the formal testing.
Statistical Test of Hypothesis	p-Value	0.3648
	Comments
	Method	Log Rank
	Comments	Log-rank test stratified according to the cytogenetic risk at time of randomization (very good, good and intermediate vs poor and very poor).

8. Secondary Outcome

Title	MDS Cohort: Kaplan-Meier Estimate of Time to AML Transformation
Description	Participants were monitored for transformation to AML until death, lost to follow-up, withdrawal of consent for further data collection, or the end of the trial. Time to transformation to AML is defined as the time from the date of randomization until the date the participant had documented transformation to AML (defined as at least 30% of myeloblasts in the bone marrow). Participants with no transformation to AML were censored at the date of their last disease assessment.
Time Frame	From randomization to the final analysis data cut-off date of 31 October 2018; maximum follow-up for survival was approximately 2 years.

Outcome Measure Data

Analysis Population Description

Participants randomized in the MDS cohort.

Arm/Group Title	MDS: Azacitidine + Durvalumab	MDS: Azacitidine Alone
Arm/Group Description	Participants with MDS received 75 mg/m² subcutaneous azacitidine (AZA) for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab (DUR) on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Measure Participants	42	42
Median (95% Confidence Interval) [months]	19.6	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MDS: Azacitidine + Durvalumab, MDS: Azacitidine Alone
	Comments
	Type of Statistical Test	Other
	Comments	P-values were not part of the formal testing.
Statistical Test of Hypothesis	p-Value	0.9528
	Comments
	Method	Log Rank
	Comments	Log-rank test stratified according to the cytogenetic risk at time of randomization (very good, good and intermediate vs poor and very poor).

9. Secondary Outcome

Title	MDS Cohort: Percentage of Participants With Disease Transformation to AML
Description	Disease transformation to AML is defined as at least 30% myeloblasts in the bone marrow. Participants were monitored for transformation to AML until death, lost to follow-up, withdrawal of consent for further data collection, or the end of the trial.
Time Frame	From randomization to the final analysis data cut-off date of 31 October 2018; maximum follow-up for survival was approximately 2 years.

Outcome Measure Data

Analysis Population Description

Participants randomized in the MDS cohort

Arm/Group Title	MDS: Azacitidine + Durvalumab	MDS: Azacitidine Alone
Arm/Group Description	Participants with MDS received 75 mg/m² subcutaneous azacitidine (AZA) for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab (DUR) on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Measure Participants	42	42
Number [percentage of participants]	23.8 56.7%	16.7 39.8%

10. Secondary Outcome

Title	AML Cohort: Kaplan Meier Estimate of Time to First Response
Description	Time to first response is defined as the time between the date of randomization and the earliest date any response (CR or CRi) was observed based on modified IWG 2003 response criteria for AML and central review. Participants who did not achieve any defined response were censored at the date of last adequate response assessment, disease progression, or death, whichever occurred first.
Time Frame	Response was assessed following every 3 treatment cycles until treatment discontinuation; median duration of treatment was 198 days (AZA) and 171 days (DUR) in the AZA + DUR group and 203 days in the AZA alone group.

Outcome Measure Data

Analysis Population Description

Participants randomized in the AML cohort

Arm/Group Title	AML: Azacitidine + Durvalumab	AML: Azacitidine Alone
Arm/Group Description	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Measure Participants	64	65
Median (95% Confidence Interval) [weeks]	NA	25.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MDS: Azacitidine + Durvalumab, MDS: Azacitidine Alone
	Comments
	Type of Statistical Test	Other
	Comments	P-values were not part of the formal testing.
Statistical Test of Hypothesis	p-Value	0.2409
	Comments
	Method	Log Rank
	Comments	Log-rank test stratified according to the cytogenetic risk at time of randomization (very intermediate vs poor).

11. Secondary Outcome

Title	AML Cohort: Kaplan Meier Estimate of Relapse-free Survival
Description	Relapse-free survival is defined as time from the date of first documented response (CR and CRi) to the date of disease relapse or death from any cause, whichever occurred first based on modified IWG 2003 response criteria for AML and central review. Participants who were still alive and progression-free were censored at the date of their last response assessment. Participants who received a subsequent therapy before the date of disease relapse or death were censored at the time of subsequent therapy.
Time Frame	From randomization to the final analysis data cut-off date of 31 October 2018; maximum follow-up for survival was approximately 2 years.

Outcome Measure Data

Analysis Population Description

Participants randomized in the AML cohort with a response (CR or CRi)

Arm/Group Title	AML: Azacitidine + Durvalumab	AML: Azacitidine Alone
Arm/Group Description	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Measure Participants	20	23
Median (95% Confidence Interval) [months]	9.5	12.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MDS: Azacitidine + Durvalumab, MDS: Azacitidine Alone
	Comments
	Type of Statistical Test	Other
	Comments	P-values were not part of the formal testing.
Statistical Test of Hypothesis	p-Value	0.2092
	Comments
	Method	Log Rank
	Comments	Log-rank test stratified according to the cytogenetic risk at time of randomization (intermediate vs poor).

12. Secondary Outcome

Title	AML Cohort: Percentage of Participants Who Achieved a Complete Cytogenetic Response
Description	Complete cytogenetic response (CyCR) based on modified IWG 2003 response criteria is defined as morphologic complete remission with a reversion to a normal karyotype. The following conditions must be met: • Absolute neutrophil count (ANC) ≥ 1.0 x10⁹/L • Platelet count ≥ 100 x10⁹/L • The bone marrow should contain less than 5% blast cells; • Auer rods should not be detectable; • No platelet, or whole blood transfusions for 7days prior to the date of the hematology assessment. AND • Reversion to normal karyotype at time of CR (based on ≥ 10 metaphases).
Time Frame	Response was assessed following every 3 treatment cycles until treatment discontinuation; median duration of treatment was 198 days (AZA) and 171 days (DUR) in the AZA + DUR group and 203 days in the AZA alone group.

Outcome Measure Data

Analysis Population Description

Participants randomized in the AML cohort evaluable for cytogenetic response (ie participants with baseline cytogenetic abnormalities).

Arm/Group Title	AML: Azacitidine + Durvalumab	AML: Azacitidine Alone
Arm/Group Description	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Measure Participants	53	50
Number (95% Confidence Interval) [percentage of participants]	11.3 26.9%	16.0 38.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MDS: Azacitidine + Durvalumab, MDS: Azacitidine Alone
	Comments
	Type of Statistical Test	Other
	Comments	P-values were not part of the formal testing.
Statistical Test of Hypothesis	p-Value	0.4894
	Comments
	Method	Wald asymptotic two-sided test
	Comments

13. Secondary Outcome

Title	AML Cohort: Percentage of Participants With Hematologic Improvement
Description	Hematological improvement was defined as participants with a erythroid response (HI-E), platelet response (HI-P) or neutrophil response (HI-NE) for at least 8 weeks, according to the IWG 2006 response criteria: Hi-E (in participants with pretreatment hemoglobin < 11 g/dL or red blood cell (RBC)-transfusion dependent): Hemoglobin increase of ≥ 1.5 g/dL, or reduction in units of RBC transfusions of at least 4 RBC transfusions/8 weeks compared with the 8 weeks prior to pretreatment. HI-P (in participants with pretreatment platelet count < 100 × 10⁹/L): Absolute increase in platelets of ≥ 30 × 10⁹/L if pretreatment value > 20 × 10⁹/L or increase from < 20 × 10⁹/L to > 20 × 10⁹/L and by at least 100%. HI-N (in participants with pretreatment neutrophils < 1.0 × 10⁹/L): At least 100% increase in neutrophils and an absolute increase of > 0.5 × 10⁹/L.
Time Frame	Response was assessed following every 3 treatment cycles until treatment discontinuation; median duration of treatment was 198 days (AZA) and 171 days (DUR) in the AZA + DUR group and 203 days in the AZA alone group.

Outcome Measure Data

Analysis Population Description

Participants randomized in the AML cohort (the percentage of participants with hematologic improvement was a pre-specified secondary endpoint for the AML cohort only).

Arm/Group Title	AML: Azacitidine + Durvalumab	AML: Azacitidine Alone
Arm/Group Description	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Measure Participants	64	65
Number (95% Confidence Interval) [percentage of participants]	42.2 100.5%	38.5 91.7%

14. Secondary Outcome

Title	AML Cohort: Kaplan-Meier Estimate of Duration of Response
Description	Duration of response is defined as the time from the first response (CR or CRi) was observed until relapse, PD, or death based on the IWG 2003 response criteria and central review. If no relapse, PD, or death was observed, the duration of response was censored at the last response assessment date that the participant was known to be progression-free.
Time Frame	Response was assessed following every 3 treatment cycles until treatment discontinuation; median duration of treatment was 198 days (AZA) and 171 days (DUR) in the AZA + DUR group and 203 days in the AZA alone group.

Outcome Measure Data

Analysis Population Description

Participants randomized in the AML cohort with an objective response (CR or CRi)

Arm/Group Title	AML: Azacitidine + Durvalumab	AML: Azacitidine Alone
Arm/Group Description	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Measure Participants	20	23
Median (95% Confidence Interval) [weeks]	24.6	51.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MDS: Azacitidine + Durvalumab, MDS: Azacitidine Alone
	Comments
	Type of Statistical Test	Other
	Comments	P-values were not part of the formal testing.
Statistical Test of Hypothesis	p-Value	0.0765
	Comments
	Method	Log Rank
	Comments	Log-rank test stratified according to the cytogenetic risk at time of randomization (intermediate vs poor).

15. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Description	Treatment emergent adverse events are adverse events (AEs) that occurred or worsened on or after the first dose of study drug (durvalumab or azacitidine) and within 90 days after last dose of durvalumab or 28 days after last dose of azacitidine. A treatment-related TEAE is a TEAE where the causal relationship was assessed by the investigator as "Suspected". The intensity of AEs was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03: Grade 1 (Mild): asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 (Moderate): minimal, local or noninvasive intervention indicated; limiting age-appropriate activities of daily living. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death due to AE.
Time Frame	MDS cohort: up to 776 days in the AZA + DUR arm and 679 days in the AZA alone arm; AML cohort: up to 840 days in the AZA + DUR arm and 656 days in the AZA alone arm.

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of any study drug.

Arm/Group Title	MDS: Azacitidine + Durvalumab	MDS: Azacitidine Alone	AML: Azacitidine + Durvalumab	AML: Azacitidine Alone
Arm/Group Description	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Measure Participants	38	41	64	62
Any treatment-emergent adverse event (TEAE)	38 90.5%	41 97.6%	64 100%	61 93.8%
TEAE related to DUR	27 64.3%	50 119%
TEAE related to AZA	31 73.8%	33 78.6%	56 87.5%	50 76.9%
TEAE related to DUR or AZA	35 83.3%	33 78.6%	58 90.6%	50 76.9%
Grade 3 TEAE	36 85.7%	30 71.4%	60 93.8%	50 76.9%
Grade 3 TEAE related to DUR	18 42.9%	29 69%
Grade 3 TEAE related to AZA	17 40.5%	16 38.1%	32 50%	27 41.5%
Grade 3 TEAE related to DUR or AZA	22 52.4%	16 38.1%	38 59.4%	27 41.5%
Grade 4 TEAE	32 76.2%	27 64.3%	43 67.2%	34 52.3%
Grade 4 TEAE related to DUR	16 38.1%	18 42.9%
Grade 4 TEAE related to AZA	19 45.2%	15 35.7%	27 42.2%	17 26.2%
Grade 4 TEAE related to DUR or AZA	22 52.4%	15 35.7%	28 43.8%	17 26.2%
Grade 5 TEAE	10 23.8%	7 16.7%	24 37.5%	11 16.9%
Grade 5 TEAE related to DUR	2 4.8%	1 2.4%
Grade 5 TEAE related to AZA	1 2.4%	1 2.4%	1 1.6%	1 1.5%
Grade 5 TEAE related to DUR or AZA	2 4.8%	1 2.4%	1 1.6%	1 1.5%
Serious TEAE	33 78.6%	27 64.3%	56 87.5%	44 67.7%
Serious TEAE related to DUR	11 26.2%	33 78.6%
Serious TEAE related to AZA	9 21.4%	10 23.8%	25 39.1%	15 23.1%
Serious TEAE related to DUR or AZA	14 33.3%	10 23.8%	34 53.1%	15 23.1%
TEAE leading to discontinuation of DUR	5 11.9%	20 47.6%
TEAE leading to discontinuation of AZA	0 0%	1 2.4%	12 18.8%	2 3.1%
TEAE leading to discontinuation of DUR or AZA	5 11.9%	1 2.4%	21 32.8%	2 3.1%
TEAE leading to dose reduction of AZA	3 7.1%	6 14.3%	10 15.6%	2 3.1%
TEAE leading to dose interruption of DUR	24 57.1%	34 81%
TEAE leading to dose interruption of AZA	27 64.3%	19 45.2%	39 60.9%	32 49.2%
TEAE leading to dose interruption of DUR or AZA	28 66.7%	19 45.2%	41 64.1%	32 49.2%
TEAE leading to ongoing DUR infusion interruption	2 4.8%	2 4.8%

16. Secondary Outcome

Title	Kaplan-Meier Estimate of Overall Survival
Description	Overall survival is defined as the time between randomization and death/censored date. Participants who were alive at the time of the clinical data cut-off were censored at the last known alive date.
Time Frame	From randomization to the final analysis data cut-off date of 31 October 2018; maximum follow-up for survival was approximately 2 years.

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	MDS: Azacitidine + Durvalumab	MDS: Azacitidine Alone	AML: Azacitidine + Durvalumab	AML: Azacitidine Alone
Arm/Group Description	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Measure Participants	42	42	64	65
Median (95% Confidence Interval) [months]	11.6	16.7	13.0	14.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MDS: Azacitidine + Durvalumab, MDS: Azacitidine Alone
	Comments
	Type of Statistical Test	Other
	Comments	P-values were not part of the formal testing.
Statistical Test of Hypothesis	p-Value	0.7374
	Comments
	Method	Log Rank
	Comments	Log-rank test stratified according to the cytogenetic risk at time of randomization (very good, good and intermediate vs poor and very poor).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	AML: Azacitidine + Durvalumab, AML: Azacitidine Alone
	Comments
	Type of Statistical Test	Other
	Comments	P-values were not part of the formal testing.
Statistical Test of Hypothesis	p-Value	0.1998
	Comments
	Method	Log Rank
	Comments	Log-rank test stratified according to the cytogenetic risk at time of randomization (intermediate vs poor).

17. Secondary Outcome

Title	One-year Survival
Description	One-year survival is defined as the probability of survival at 1 year from randomization and is represented by the Kaplan-Meier estimate of the percentage of participants alive after 1 year.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	MDS: Azacitidine + Durvalumab	MDS: Azacitidine Alone	AML: Azacitidine + Durvalumab	AML: Azacitidine Alone
Arm/Group Description	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Measure Participants	42	42	64	65
Number [percentage of participants]	49 116.7%	57 135.7%	52 81.3%	55 84.6%

18. Secondary Outcome

Title	Durvalumab Serum Concentration
Time Frame	Cycle 1 Day 1 end of infusion (EOI), Cycle 2 Day 1 pre-infusion, Cycle 4 Day 1 pre-infusion and EOI, and Cycle 6 Day 1 pre-infusion

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of durvalumab and who had at least 1 measurable durvalumab concentration value and with available data at each time point.

Arm/Group Title	MDS: Azacitidine + Durvalumab	AML: Azacitidine + Durvalumab
Arm/Group Description	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.	Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Measure Participants	38	62
Cycle 1 Day 1 end of infusion	375548.511 (140777.0558)	378598.369 (201902.4363)
Cycle 2 Day 1 pre-infusion	84380.032 (92174.3455)	54216.956 (28336.3692)
Cycle 4 Day 1 pre-infusion	132266.794 (126971.6223)	78622.429 (41708.9956)
Cycle 4 Day 1 end of infusion	433942.600 (233241.0329)	391523.395 (147928.1261)
Cycle 6 Day 1 pre-infusion	114448.977 (64608.9007)	142517.871 (248212.8037)

Adverse Events

Time Frame	All-cause mortality is reported through the end of follow-up for survival, as of the data cut-off date of 31 October 2018; up to approximately 2 years. Adverse events are reported from first dose of study drug (durvalumab or azacitidine) up to 90 days after last dose of durvalumab or 28 days after last dose of azacitidine: MDS cohort: up to 776 days in the AZA + DUR arm and 679 days in the AZA alone arm; AML cohort: up to 840 days in the AZA + DUR arm and 656 days in the AZA alone arm.
Arm/Group Title	MDS: Azacitidine + Durvalumab		MDS: Azacitidine Alone		AML: Azacitidine + Durvalumab		AML: Azacitidine Alone
Arm/Group Description	Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.		Participants with MDS received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.		Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.		Participants with AML received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
All Cause Mortality
	MDS: Azacitidine + Durvalumab		MDS: Azacitidine Alone		AML: Azacitidine + Durvalumab		AML: Azacitidine Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/38 (52.6%)		21/41 (51.2%)		42/64 (65.6%)		39/62 (62.9%)
Serious Adverse Events
	MDS: Azacitidine + Durvalumab		MDS: Azacitidine Alone		AML: Azacitidine + Durvalumab		AML: Azacitidine Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/38 (86.8%)		27/41 (65.9%)		56/64 (87.5%)		44/62 (71%)
Blood and lymphatic system disorders
Anaemia	3/38 (7.9%)		1/41 (2.4%)		3/64 (4.7%)		1/62 (1.6%)
Cytopenia	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Febrile neutropenia	14/38 (36.8%)		9/41 (22%)		23/64 (35.9%)		14/62 (22.6%)
Leukocytosis	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Neutropenia	4/38 (10.5%)		2/41 (4.9%)		3/64 (4.7%)		1/62 (1.6%)
Thrombocytopenia	1/38 (2.6%)		0/41 (0%)		3/64 (4.7%)		1/62 (1.6%)
Cardiac disorders
Acute myocardial infarction	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Atrial fibrillation	1/38 (2.6%)		0/41 (0%)		1/64 (1.6%)		1/62 (1.6%)
Atrial flutter	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Cardiac arrest	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Cardiac failure	0/38 (0%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Cardiac failure chronic	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Cardiogenic shock	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Myocardial infarction	0/38 (0%)		1/41 (2.4%)		0/64 (0%)		1/62 (1.6%)
Myocarditis	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Endocrine disorders
Autoimmune thyroiditis	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Eye disorders
Diplopia	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Gastrointestinal disorders
Abdominal pain	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		2/62 (3.2%)
Acute abdomen	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Anal fistula	0/38 (0%)		1/41 (2.4%)		2/64 (3.1%)		0/62 (0%)
Autoimmune colitis	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Colitis	2/38 (5.3%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Constipation	0/38 (0%)		0/41 (0%)		3/64 (4.7%)		1/62 (1.6%)
Diarrhoea	3/38 (7.9%)		1/41 (2.4%)		3/64 (4.7%)		1/62 (1.6%)
Enteritis	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Faecaloma	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Gastric ulcer haemorrhage	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Gastrointestinal haemorrhage	0/38 (0%)		1/41 (2.4%)		2/64 (3.1%)		1/62 (1.6%)
Haematochezia	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Intestinal ischaemia	0/38 (0%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Lower gastrointestinal haemorrhage	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Melaena	0/38 (0%)		0/41 (0%)		2/64 (3.1%)		1/62 (1.6%)
Mouth haemorrhage	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Nausea	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		1/62 (1.6%)
Small intestinal obstruction	0/38 (0%)		1/41 (2.4%)		1/64 (1.6%)		0/62 (0%)
Stomatitis	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Upper gastrointestinal haemorrhage	1/38 (2.6%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Vomiting	0/38 (0%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
General disorders
Asthenia	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
General physical health deterioration	2/38 (5.3%)		0/41 (0%)		8/64 (12.5%)		4/62 (6.5%)
Generalised oedema	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Granuloma	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Injection site haemorrhage	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Injection site reaction	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Injection site vesicles	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Mucosal inflammation	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Multiple organ dysfunction syndrome	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Non-cardiac chest pain	1/38 (2.6%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Pyrexia	5/38 (13.2%)		3/41 (7.3%)		8/64 (12.5%)		5/62 (8.1%)
Sudden death	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Hepatobiliary disorders
Cholecystitis	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Cholelithiasis	0/38 (0%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Hepatic cirrhosis	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Hypertransaminasaemia	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Infections and infestations
Anal abscess	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Appendicitis	0/38 (0%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Arthritis bacterial	0/38 (0%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Aspergillus infection	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Atypical pneumonia	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Bacteraemia	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		1/62 (1.6%)
Bacterial infection	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Breast abscess	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Bronchitis	1/38 (2.6%)		0/41 (0%)		2/64 (3.1%)		2/62 (3.2%)
Bronchopulmonary aspergillosis	1/38 (2.6%)		0/41 (0%)		2/64 (3.1%)		0/62 (0%)
Cellulitis	1/38 (2.6%)		0/41 (0%)		3/64 (4.7%)		1/62 (1.6%)
Clostridium difficile colitis	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Cystitis	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Device related infection	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Diverticulitis	1/38 (2.6%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Endocarditis	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Enterococcal bacteraemia	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Enterococcal infection	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Escherichia sepsis	1/38 (2.6%)		0/41 (0%)		1/64 (1.6%)		1/62 (1.6%)
Escherichia urinary tract infection	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Febrile infection	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Gastroenteritis viral	0/38 (0%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Gastrointestinal infection	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Gingivitis	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Infection	0/38 (0%)		1/41 (2.4%)		3/64 (4.7%)		0/62 (0%)
Influenza	1/38 (2.6%)		1/41 (2.4%)		2/64 (3.1%)		0/62 (0%)
Injection site infection	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Lower respiratory tract infection	1/38 (2.6%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Lower respiratory tract infection fungal	1/38 (2.6%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Lung infection	1/38 (2.6%)		0/41 (0%)		1/64 (1.6%)		1/62 (1.6%)
Metapneumovirus infection	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Micrococcus infection	0/38 (0%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Neutropenic infection	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Neutropenic sepsis	1/38 (2.6%)		1/41 (2.4%)		1/64 (1.6%)		2/62 (3.2%)
Oesophageal infection	0/38 (0%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Perineal cellulitis	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Pneumocystis jirovecii pneumonia	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		1/62 (1.6%)
Pneumonia	6/38 (15.8%)		3/41 (7.3%)		15/64 (23.4%)		8/62 (12.9%)
Pneumonia fungal	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		1/62 (1.6%)
Pneumonia influenzal	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Pneumonia viral	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Progressive multifocal leukoencephalopathy	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Pseudomonal sepsis	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Pulmonary sepsis	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Pyelonephritis	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Rectal abscess	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Respiratory tract infection	1/38 (2.6%)		0/41 (0%)		2/64 (3.1%)		0/62 (0%)
Sepsis	1/38 (2.6%)		3/41 (7.3%)		4/64 (6.3%)		4/62 (6.5%)
Septic shock	2/38 (5.3%)		0/41 (0%)		2/64 (3.1%)		1/62 (1.6%)
Serratia sepsis	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Skin infection	0/38 (0%)		2/41 (4.9%)		0/64 (0%)		1/62 (1.6%)
Staphylococcal abscess	0/38 (0%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Streptococcal sepsis	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Superinfection bacterial	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Tonsillitis	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Upper respiratory tract infection	1/38 (2.6%)		0/41 (0%)		1/64 (1.6%)		1/62 (1.6%)
Urinary tract infection	3/38 (7.9%)		0/41 (0%)		1/64 (1.6%)		2/62 (3.2%)
Vascular device infection	0/38 (0%)		0/41 (0%)		2/64 (3.1%)		0/62 (0%)
Viral upper respiratory tract infection	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Injury, poisoning and procedural complications
Fall	0/38 (0%)		0/41 (0%)		2/64 (3.1%)		0/62 (0%)
Femur fracture	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Lumbar vertebral fracture	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Spinal fracture	1/38 (2.6%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Synovial rupture	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Transfusion reaction	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Traumatic fracture	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		1/62 (1.6%)
Traumatic intracranial haemorrhage	0/38 (0%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Investigations
Platelet count decreased	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Metabolism and nutrition disorders
Fluid retention	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Gout	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Hypophagia	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Lactic acidosis	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Arthritis	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Back pain	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Muscle haemorrhage	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	2/38 (5.3%)		0/41 (0%)		1/64 (1.6%)		1/62 (1.6%)
Transformation to acute myeloid leukaemia	3/38 (7.9%)		4/41 (9.8%)		0/64 (0%)		0/62 (0%)
Tumour associated fever	0/38 (0%)		1/41 (2.4%)		1/64 (1.6%)		0/62 (0%)
Nervous system disorders
Cerebral haemorrhage	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Cerebral infarction	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Cerebrovascular accident	1/38 (2.6%)		0/41 (0%)		2/64 (3.1%)		0/62 (0%)
Depressed level of consciousness	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Encephalopathy	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Intraventricular haemorrhage	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Ischaemic stroke	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Loss of consciousness	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Lumbar radiculopathy	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Peripheral sensory neuropathy	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Seizure	0/38 (0%)		0/41 (0%)		2/64 (3.1%)		0/62 (0%)
Subarachnoid haemorrhage	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Syncope	0/38 (0%)		0/41 (0%)		2/64 (3.1%)		0/62 (0%)
Psychiatric disorders
Confusional state	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Mental status changes	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Renal and urinary disorders
Acute kidney injury	2/38 (5.3%)		1/41 (2.4%)		2/64 (3.1%)		2/62 (3.2%)
Calculus bladder	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Renal failure	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		1/62 (1.6%)
Urinary retention	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Reproductive system and breast disorders
Female genital tract fistula	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Prostatitis	0/38 (0%)		0/41 (0%)		2/64 (3.1%)		0/62 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Cough	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Dyspnoea	1/38 (2.6%)		0/41 (0%)		1/64 (1.6%)		1/62 (1.6%)
Epistaxis	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		1/62 (1.6%)
Hypoxia	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Interstitial lung disease	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Lung infiltration	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Pleural effusion	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Pneumonitis	1/38 (2.6%)		0/41 (0%)		5/64 (7.8%)		1/62 (1.6%)
Productive cough	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Pulmonary embolism	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Pulmonary oedema	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Respiratory failure	0/38 (0%)		0/41 (0%)		2/64 (3.1%)		1/62 (1.6%)
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Panniculitis	0/38 (0%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Pemphigoid	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Rash	0/38 (0%)		0/41 (0%)		2/64 (3.1%)		0/62 (0%)
Skin lesion	0/38 (0%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Skin ulcer	0/38 (0%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Toxic skin eruption	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Vascular disorders
Haematoma	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Haemorrhage	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Hypotension	1/38 (2.6%)		0/41 (0%)		4/64 (6.3%)		2/62 (3.2%)
Hypovolaemic shock	1/38 (2.6%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Peripheral artery thrombosis	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Raynaud's phenomenon	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Thrombophlebitis	0/38 (0%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Venous thrombosis	0/38 (0%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Other (Not Including Serious) Adverse Events
	MDS: Azacitidine + Durvalumab		MDS: Azacitidine Alone		AML: Azacitidine + Durvalumab		AML: Azacitidine Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/38 (100%)		40/41 (97.6%)		63/64 (98.4%)		59/62 (95.2%)
Blood and lymphatic system disorders
Anaemia	13/38 (34.2%)		14/41 (34.1%)		18/64 (28.1%)		18/62 (29%)
Bone marrow failure	0/38 (0%)		3/41 (7.3%)		0/64 (0%)		0/62 (0%)
Febrile neutropenia	4/38 (10.5%)		2/41 (4.9%)		5/64 (7.8%)		8/62 (12.9%)
Leukopenia	8/38 (21.1%)		3/41 (7.3%)		6/64 (9.4%)		6/62 (9.7%)
Neutropenia	23/38 (60.5%)		21/41 (51.2%)		20/64 (31.3%)		21/62 (33.9%)
Thrombocytopenia	19/38 (50%)		18/41 (43.9%)		24/64 (37.5%)		27/62 (43.5%)
Cardiac disorders
Angina pectoris	2/38 (5.3%)		0/41 (0%)		2/64 (3.1%)		3/62 (4.8%)
Atrial fibrillation	4/38 (10.5%)		0/41 (0%)		3/64 (4.7%)		2/62 (3.2%)
Tachycardia	4/38 (10.5%)		2/41 (4.9%)		4/64 (6.3%)		1/62 (1.6%)
Ear and labyrinth disorders
Ear pain	2/38 (5.3%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Gastrointestinal disorders
Abdominal discomfort	0/38 (0%)		0/41 (0%)		0/64 (0%)		4/62 (6.5%)
Abdominal pain	3/38 (7.9%)		1/41 (2.4%)		6/64 (9.4%)		6/62 (9.7%)
Constipation	22/38 (57.9%)		20/41 (48.8%)		36/64 (56.3%)		33/62 (53.2%)
Diarrhoea	16/38 (42.1%)		14/41 (34.1%)		27/64 (42.2%)		16/62 (25.8%)
Dry mouth	4/38 (10.5%)		1/41 (2.4%)		3/64 (4.7%)		1/62 (1.6%)
Dyspepsia	4/38 (10.5%)		2/41 (4.9%)		3/64 (4.7%)		2/62 (3.2%)
Gingival bleeding	2/38 (5.3%)		0/41 (0%)		6/64 (9.4%)		2/62 (3.2%)
Haemorrhoids	2/38 (5.3%)		2/41 (4.9%)		5/64 (7.8%)		5/62 (8.1%)
Mouth haemorrhage	1/38 (2.6%)		0/41 (0%)		2/64 (3.1%)		4/62 (6.5%)
Nausea	16/38 (42.1%)		11/41 (26.8%)		26/64 (40.6%)		22/62 (35.5%)
Odynophagia	2/38 (5.3%)		0/41 (0%)		0/64 (0%)		2/62 (3.2%)
Stomatitis	2/38 (5.3%)		3/41 (7.3%)		5/64 (7.8%)		4/62 (6.5%)
Vomiting	10/38 (26.3%)		10/41 (24.4%)		19/64 (29.7%)		15/62 (24.2%)
General disorders
Asthenia	9/38 (23.7%)		14/41 (34.1%)		19/64 (29.7%)		12/62 (19.4%)
Fatigue	9/38 (23.7%)		6/41 (14.6%)		17/64 (26.6%)		11/62 (17.7%)
General physical health deterioration	0/38 (0%)		3/41 (7.3%)		1/64 (1.6%)		1/62 (1.6%)
Influenza like illness	2/38 (5.3%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Injection site bruising	2/38 (5.3%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Injection site erythema	2/38 (5.3%)		2/41 (4.9%)		6/64 (9.4%)		5/62 (8.1%)
Injection site pain	3/38 (7.9%)		4/41 (9.8%)		4/64 (6.3%)		2/62 (3.2%)
Injection site rash	3/38 (7.9%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Injection site reaction	3/38 (7.9%)		4/41 (9.8%)		10/64 (15.6%)		7/62 (11.3%)
Mucosal inflammation	0/38 (0%)		3/41 (7.3%)		4/64 (6.3%)		2/62 (3.2%)
Oedema	2/38 (5.3%)		1/41 (2.4%)		6/64 (9.4%)		1/62 (1.6%)
Oedema peripheral	14/38 (36.8%)		7/41 (17.1%)		18/64 (28.1%)		8/62 (12.9%)
Pain	3/38 (7.9%)		1/41 (2.4%)		1/64 (1.6%)		2/62 (3.2%)
Pyrexia	12/38 (31.6%)		13/41 (31.7%)		23/64 (35.9%)		21/62 (33.9%)
Hepatobiliary disorders
Hyperbilirubinaemia	2/38 (5.3%)		1/41 (2.4%)		3/64 (4.7%)		1/62 (1.6%)
Infections and infestations
Cellulitis	3/38 (7.9%)		5/41 (12.2%)		6/64 (9.4%)		4/62 (6.5%)
Fungal infection	2/38 (5.3%)		1/41 (2.4%)		0/64 (0%)		1/62 (1.6%)
Gingivitis	0/38 (0%)		3/41 (7.3%)		1/64 (1.6%)		2/62 (3.2%)
Influenza	2/38 (5.3%)		1/41 (2.4%)		3/64 (4.7%)		3/62 (4.8%)
Laryngitis	2/38 (5.3%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Nasopharyngitis	4/38 (10.5%)		5/41 (12.2%)		3/64 (4.7%)		7/62 (11.3%)
Oral candidiasis	6/38 (15.8%)		0/41 (0%)		2/64 (3.1%)		3/62 (4.8%)
Oral herpes	2/38 (5.3%)		2/41 (4.9%)		4/64 (6.3%)		2/62 (3.2%)
Paronychia	2/38 (5.3%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Pharyngitis	2/38 (5.3%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Pneumonia	2/38 (5.3%)		1/41 (2.4%)		4/64 (6.3%)		7/62 (11.3%)
Tooth infection	2/38 (5.3%)		1/41 (2.4%)		2/64 (3.1%)		2/62 (3.2%)
Urinary tract infection	6/38 (15.8%)		1/41 (2.4%)		8/64 (12.5%)		4/62 (6.5%)
Vascular device infection	2/38 (5.3%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Injury, poisoning and procedural complications
Contusion	2/38 (5.3%)		4/41 (9.8%)		1/64 (1.6%)		6/62 (9.7%)
Fall	4/38 (10.5%)		4/41 (9.8%)		6/64 (9.4%)		6/62 (9.7%)
Infusion related reaction	2/38 (5.3%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Skin laceration	2/38 (5.3%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Transfusion reaction	2/38 (5.3%)		0/41 (0%)		2/64 (3.1%)		4/62 (6.5%)
Investigations
Alanine aminotransferase increased	8/38 (21.1%)		2/41 (4.9%)		2/64 (3.1%)		3/62 (4.8%)
Aspartate aminotransferase increased	2/38 (5.3%)		0/41 (0%)		0/64 (0%)		3/62 (4.8%)
Blood alkaline phosphatase increased	4/38 (10.5%)		0/41 (0%)		3/64 (4.7%)		2/62 (3.2%)
Blood bilirubin increased	4/38 (10.5%)		1/41 (2.4%)		4/64 (6.3%)		1/62 (1.6%)
Blood creatinine increased	6/38 (15.8%)		2/41 (4.9%)		6/64 (9.4%)		3/62 (4.8%)
Gamma-glutamyltransferase increased	2/38 (5.3%)		1/41 (2.4%)		3/64 (4.7%)		0/62 (0%)
Weight decreased	2/38 (5.3%)		5/41 (12.2%)		9/64 (14.1%)		5/62 (8.1%)
Metabolism and nutrition disorders
Decreased appetite	8/38 (21.1%)		7/41 (17.1%)		18/64 (28.1%)		10/62 (16.1%)
Gout	2/38 (5.3%)		1/41 (2.4%)		1/64 (1.6%)		1/62 (1.6%)
Hyperglycaemia	5/38 (13.2%)		3/41 (7.3%)		2/64 (3.1%)		1/62 (1.6%)
Hypoalbuminaemia	3/38 (7.9%)		3/41 (7.3%)		2/64 (3.1%)		4/62 (6.5%)
Hypocalcaemia	7/38 (18.4%)		0/41 (0%)		3/64 (4.7%)		4/62 (6.5%)
Hypokalaemia	5/38 (13.2%)		2/41 (4.9%)		13/64 (20.3%)		11/62 (17.7%)
Hypomagnesaemia	4/38 (10.5%)		4/41 (9.8%)		5/64 (7.8%)		3/62 (4.8%)
Hyponatraemia	6/38 (15.8%)		3/41 (7.3%)		2/64 (3.1%)		3/62 (4.8%)
Hypophosphataemia	4/38 (10.5%)		1/41 (2.4%)		5/64 (7.8%)		4/62 (6.5%)
Hypoproteinaemia	2/38 (5.3%)		0/41 (0%)		0/64 (0%)		1/62 (1.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/38 (10.5%)		3/41 (7.3%)		11/64 (17.2%)		6/62 (9.7%)
Arthritis	2/38 (5.3%)		1/41 (2.4%)		2/64 (3.1%)		2/62 (3.2%)
Back pain	4/38 (10.5%)		6/41 (14.6%)		15/64 (23.4%)		5/62 (8.1%)
Muscle tightness	2/38 (5.3%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Muscular weakness	2/38 (5.3%)		0/41 (0%)		3/64 (4.7%)		1/62 (1.6%)
Musculoskeletal pain	4/38 (10.5%)		1/41 (2.4%)		8/64 (12.5%)		3/62 (4.8%)
Myalgia	2/38 (5.3%)		1/41 (2.4%)		1/64 (1.6%)		1/62 (1.6%)
Neck pain	2/38 (5.3%)		1/41 (2.4%)		1/64 (1.6%)		1/62 (1.6%)
Pain in extremity	1/38 (2.6%)		2/41 (4.9%)		12/64 (18.8%)		3/62 (4.8%)
Nervous system disorders
Dizziness	6/38 (15.8%)		8/41 (19.5%)		6/64 (9.4%)		4/62 (6.5%)
Headache	8/38 (21.1%)		3/41 (7.3%)		6/64 (9.4%)		7/62 (11.3%)
Peripheral sensory neuropathy	0/38 (0%)		1/41 (2.4%)		4/64 (6.3%)		3/62 (4.8%)
Sciatica	2/38 (5.3%)		1/41 (2.4%)		0/64 (0%)		2/62 (3.2%)
Syncope	3/38 (7.9%)		2/41 (4.9%)		2/64 (3.1%)		0/62 (0%)
Psychiatric disorders
Anxiety	3/38 (7.9%)		2/41 (4.9%)		1/64 (1.6%)		3/62 (4.8%)
Confusional state	1/38 (2.6%)		0/41 (0%)		2/64 (3.1%)		4/62 (6.5%)
Insomnia	9/38 (23.7%)		4/41 (9.8%)		11/64 (17.2%)		8/62 (12.9%)
Renal and urinary disorders
Acute kidney injury	4/38 (10.5%)		0/41 (0%)		5/64 (7.8%)		1/62 (1.6%)
Dysuria	2/38 (5.3%)		1/41 (2.4%)		0/64 (0%)		3/62 (4.8%)
Urinary incontinence	2/38 (5.3%)		1/41 (2.4%)		1/64 (1.6%)		1/62 (1.6%)
Urinary retention	2/38 (5.3%)		0/41 (0%)		3/64 (4.7%)		1/62 (1.6%)
Respiratory, thoracic and mediastinal disorders
Cough	13/38 (34.2%)		11/41 (26.8%)		18/64 (28.1%)		16/62 (25.8%)
Dyspnoea	9/38 (23.7%)		4/41 (9.8%)		15/64 (23.4%)		12/62 (19.4%)
Dyspnoea exertional	3/38 (7.9%)		0/41 (0%)		3/64 (4.7%)		0/62 (0%)
Epistaxis	6/38 (15.8%)		4/41 (9.8%)		13/64 (20.3%)		5/62 (8.1%)
Oropharyngeal pain	2/38 (5.3%)		4/41 (9.8%)		4/64 (6.3%)		3/62 (4.8%)
Pharyngeal erythema	2/38 (5.3%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Productive cough	2/38 (5.3%)		0/41 (0%)		1/64 (1.6%)		0/62 (0%)
Rhinorrhoea	0/38 (0%)		3/41 (7.3%)		1/64 (1.6%)		1/62 (1.6%)
Upper-airway cough syndrome	2/38 (5.3%)		0/41 (0%)		0/64 (0%)		0/62 (0%)
Skin and subcutaneous tissue disorders
Dry skin	5/38 (13.2%)		2/41 (4.9%)		2/64 (3.1%)		1/62 (1.6%)
Ecchymosis	1/38 (2.6%)		1/41 (2.4%)		1/64 (1.6%)		4/62 (6.5%)
Erythema	2/38 (5.3%)		3/41 (7.3%)		5/64 (7.8%)		5/62 (8.1%)
Night sweats	2/38 (5.3%)		1/41 (2.4%)		0/64 (0%)		0/62 (0%)
Petechiae	3/38 (7.9%)		0/41 (0%)		3/64 (4.7%)		2/62 (3.2%)
Pruritus	5/38 (13.2%)		5/41 (12.2%)		8/64 (12.5%)		6/62 (9.7%)
Rash	7/38 (18.4%)		3/41 (7.3%)		10/64 (15.6%)		4/62 (6.5%)
Rash erythematous	3/38 (7.9%)		0/41 (0%)		2/64 (3.1%)		0/62 (0%)
Rash maculo-papular	3/38 (7.9%)		0/41 (0%)		2/64 (3.1%)		0/62 (0%)
Skin lesion	3/38 (7.9%)		2/41 (4.9%)		3/64 (4.7%)		2/62 (3.2%)
Urticaria	2/38 (5.3%)		2/41 (4.9%)		1/64 (1.6%)		1/62 (1.6%)
Vascular disorders
Hypertension	2/38 (5.3%)		2/41 (4.9%)		4/64 (6.3%)		4/62 (6.5%)
Hypotension	4/38 (10.5%)		2/41 (4.9%)		7/64 (10.9%)		8/62 (12.9%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Results from a center cannot be submitted for publication before results of multicenter study are published unless it is > 1 year since study completion. Then, Investigator can publish if manuscript is submitted to Celgene 60 days prior to submission. If Celgene decides publication would hinder drug development, Investigator must delay submission for up to 90 additional days. Investigator must delete confidential information before submission and defer publication to permit patent applications.