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)

Celgene213 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

213

Conditions

Leukemia, Myeloid, Acute Myelodysplastic Syndromes

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: For both cohorts: 1. Subject must understand and voluntarily sign an informed consent form (ICF) prior to any study-related assessments/procedures being conducted. 2. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 3. Female subjects of childbearing potential may participate, providing they meet the following conditions: 1. Have 2 negative pregnancy tests as verified by the Investigator prior to starting any investigational product (IP) therapy: serum pregnancy test at screening and negative serum or urine pregnancy test (Investigator's discretion) within 72 hours prior to starting treatment with IP (Cycle 1, Day 1). They must agree to ongoing pregnancy testing during the course of the study (before beginning each subsequent cycle of treatment), and after the last dose of any IP. This applies even if the subject practices complete abstinence from heterosexual contact. 2. Agree to practice true abstinence (which must be reviewed on a monthly basis and source documented) or agree to the use of a highly effective method of contraception use from 28 days prior to starting durvalumab or azacitidine, and must agree to continue using such precautions while taking durvalumab or azacitidine (including dose interruptions) and up to 90 days after the last dose of durvalumab or azacitidine. Cessation of contraception after this point should be discussed with a responsible physician. 3. Agree to abstain from breastfeeding during study participation and for at least 90 days after the last dose of IP. 4. Refrain from egg cell donation while taking durvalumab and for at least 90 days after the last dose of durvalumab. 4. Male subject must: 1. Either practice true abstinence from heterosexual contact (which must be reviewed on a monthly basis) or agree to avoid fathering a child, to use highly effective methods of contraception, male condom plus spermicide during sexual contact with a pregnant female or a female of childbearing potential (even if he has undergone a successful vasectomy) from starting dose of IP (Cycle 1 Day 1), including dose interruptions through 90 days after receipt of the last dose of durvalumab or azacitidine. 2. Refrain from semen or sperm donation while taking IP and for at least 90 days after the last dose of IP. 5. Understand and voluntarily sign a biomarker-specific component of the informed consent form prior to any study-related procedures conducted. 6. Willing and able to adhere to the study visit schedule and other protocol requirements. MDS Cohort: 7. Age ≥ 18 years at the time of signing the informed consent form. 8. Central confirmation of diagnosis of previously untreated primary or secondary myelodysplastic syndromes (MDS) as per World Health Organization (WHO) classification. Results of central pathology review are required prior to receiving the first dose of IP. 9. Central confirmation of the categorization of the MDS risk classification, as per the Revised - International prognostic scoring system (IPSS-R) Intermediate risk with \>10% blasts or poor or very poor cytogenetics, or IPSS-R High or Very High risk (results of central pathology review required prior to receiving the first dose of IP). Acute myeloid leukemia (AML) Cohort: 10. Age ≥ 65 years at the time of signing the informed consent form (ICF). 11. Central confirmation of diagnosis of one of the following untreated AML as per WHO classification: * Newly diagnosed, histologically confirmed de novo AML (bone marrow blasts ≥ 20%), or * AML secondary to prior MDS, or * AML secondary to exposure to potentially leukemogenic therapies or agents (eg, radiation therapy, alkylating agents, topoisomerase II inhibitors) with the primary malignancy in remission for at least 2 years. 12. Central confirmation of intermediate or poor risk status, based on Cytogenetics for acute myeloid leukemia. Exclusion Criteria: For both cohorts: 1. Prior hematopoietic stem cell transplant. 2. Considered eligible for hematopoietic stem cell transplant (allogeneic or autologous) at the time of signing the ICF. 3. Prior exposure to azacitidine, decitabine or prior exposure to the investigational oral formulation of decitabine, or other oral azacitidine derivative. 4. Inaspirable bone marrow. 5. Use of any of the following within 28 days prior to the first dose of IP: * Thrombopoiesis-stimulating agents (eg, romiplostim, eltrombopag, Interleukin-11) * Any hematopoietic growth factors (erythropoietin-stimulating agents \[ESAs\], granulocyte colony-stimulating factor (G-CSF) and other red blood cell (RBC) hematopoietic growth factors (eg, Interleukin-3) * Any investigational agents within 28 days or 5 half-lives (whichever is longer) of initiating study treatment 6. Prior history of malignancies (except MDS for AML subjects), unless the subject has been free of the disease for ≥ 2 years. However, subjects with the following history/concurrent conditions are allowed: * Basal or squamous cell carcinoma of the skin * Carcinoma in situ of the cervix * Carcinoma in situ of the breast * Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis \[tumor, node, metastases (TNM)\] clinical staging system). 7. Pregnant or breast-feeding females or females who intend to become pregnant during study participation. 8. Subject has active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[eg, colitis, Crohn's disease\], diverticulitis with the exception of a prior episode that has resolved or diverticulosis, celiac disease, irritable bowel disease \[exclude only if active within the last 6 months prior to signing the ICF\], or other serious gastrointestinal chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener's syndrome \[granulomatosis with polyangiitis\]; myasthenia gravis; Graves' disease; rheumatoid arthritis; hypophysitis, uveitis; etc) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion: * Subjects with vitiligo or alopecia; * Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement for ≥ 3 months prior to signing the ICF; or * Subjects with psoriasis not requiring systemic treatment 9. Significant active cardiac disease within the previous 6 months prior to signing the ICF, including: * New York Heart Association (NYHA) Class III or IV congestive heart failure; * Unstable angina or angina requiring surgical or medical intervention; and/or * Significant cardiac arrhythmia * Myocardial infarction 10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment), uncontrolled hypertension, cardiac arrhythmia, pneumonitis, interstitial lung disease, active peptic ulcer disease or gastritis that would limit compliance with study requirement. 11. Known human immunodeficiency virus (HIV) or hepatitis C (HCV) infection, or evidence of active hepatitis B virus (HBV) infection. 12. Known or suspected hypersensitivity to azacitidine, mannitol, or durvalumab, its constituents, or to any other humanized monoclonal antibody. 13. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study. 14. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study. 15. Prior anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death-1 (PD-1), or programmed death ligand-1 (PD-L1) or other immune checkpoint mAb exposure. 16. Other investigational monoclonal antibodies (mAbs) within 6 months prior to first dose of IP. 17. Current or prior use of immunosuppressive medication within 14 days prior to the first dose of IP. The following are exceptions to this criterion: * Intranasal, inhaled, topical, or local steroid injections (eg, intra-articular injection) * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent * Steroids as premedication for hypersensitivity reactions (eg, computed tomography \[CT\] scan premedication) 18. History of primary immunodeficiency. 19. Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP (NOTE: Subjects, if enrolled, should not receive live vaccine during the study and for 30 days after the last dose of durvalumab). 20. Unwilling or unable to complete subject reported outcome assessments without assistance or with minimal assistance from trained site personnel and/or caregiver. 21. Subjects who have had clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia. 22. Presence of advanced malignant hepatic tumors. 23. Any of the following laboratory abnormalities: * Serum aspartate aminotransferase (AST/SGOT) or alanine aminotransferase (ALT/SGPT) \> 2.5 × upper limit of normal (ULN) * Serum total bilirubin \> 1.5 × ULN. Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis). Subjects are excluded if there is evidence of autoimmune hemolytic anemia manifested as a corrected reticulocyte count of \> 2% with either a positive Coombs' test or over 50% of indirect bilirubin * Serum creatinine \> 2.5 × ULN. MDS Cohort: 24. Any previous cytotoxic, cytostatic, hormonal, biological or immunological treatment for MDS (ESA with or without G-CSF are allowed under certain conditions, see exclusion criterion # 5). 25. Any investigational therapy within 28 days prior to the first dose of IP. 26. Use of hydroxyurea within 2 weeks prior to obtaining the screening hematology sample and prior to first dose of IP. 27. Absolute white blood cell (WBC) count ≥ 15 × 10\^9/L. AML Cohort: 28. Previous cytotoxic, cytostatic, hormonal, biological or immunological treatment (ESA with or without G-CSF and iron chelating therapy and hydroxyurea are allowed under certain conditions, see exclusion criterion #5) or biologic treatment for AML. 29. Any investigational therapy within 28 days prior to the first dose of IP. 30. Use of hydroxyurea within 2 weeks prior to obtaining the screening hematology sample and prior to first dose of IP. 31. Prior use of targeted therapy agents (eg, FLT3 inhibitors, other kinase inhibitors). 32. Suspected or proven acute promyelocytic leukemia (French-American-British (FAB) M3) based on morphology, immunophenotype, molecular assay, or karyotype; AML associated with t(9;22) karyotype, biphenotypic acute leukemia or AML with previous hematologic disorder such as chronic myelogenous leukemia or myeloproliferative neoplasms. 33. Acute myeloid leukemia associated with inv(16), t(8;21), t(16;16), t(15;17) karyotypes or molecular evidence of such translocations if not associated with a c-Kit mutation. 34. Absolute WBC count ≥ 15 × 10\^⁹/L (NOTE: Hydroxyurea is not allowed to attain a WBC count ≤ 15 x 10⁹/L). 35. Known history or presence of Sweet Syndrome at screening

Locations (103)

Yale Cancer Center

New Haven, Connecticut, United States

Georgetown University Hospital

Washington D.C., District of Columbia, United States

University of Florida

Gainesville, Florida, United States

Moffitt Cancer Center

Tampa, Florida, United States

University of Chicago

Chicago, Illinois, United States

Outcomes

Primary Outcomes

MDS Cohort: Overall Response Rate

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.

AML Cohort: Overall Response Rate

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.

Secondary Outcomes

MDS Cohort: Kaplan Meier Estimate of Time to First Response

Time to first response is defined as the time from randomization to the earliest date any response (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. 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. Response was assessed following every 3 treatment cycles until treatment discontinuation.

Time frame: From randomization to the earliest date any response (up to approximately 34 months)

MDS Cohort: Kaplan Meier Estimate of Relapse-free Survival

Relapse-free survival is defined as the time from the date of first documented response (complete remission (CR), partial remission (PR)) to the date of disease relapse or death from any cause, whichever occurred first according to the International Working Group (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. Response was assessed following every 3 treatment cycles until treatment discontinuation.

Time frame: From randomization to to the date of disease relapse or death from any cause, whichever occurred first (up to approximately 34 months)

MDS Cohort: Percentage of Participants Who Achieved a Cytogenetic Response

Cytogenetic response is defined as the percentage of participants who achieved a complete cytogenetic response or partial cytogenetic response according to the International Working Group (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. Response was assessed following every 3 treatment cycles until treatment discontinuation.

Time frame: From randomization up to approximately 34 months

MDS Cohort: Kaplan-Meier Estimate of Progression-free Survival (PFS)

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 the International Working Group (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 first documented progressive disease (PD), relapse, or death due to any cause (up to approximately 34 months)

MDS Cohort: Kaplan-Meier Estimate of Duration of Response

Duration of response is defined as the time from when the first overall response (complete remission (CR), partial remission (PR), marrow complete remission (mCR), and/or hematological improvement (HI)) was observed until relapse, progressive disease (PD), or death, as defined by the International Working Group (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. Response was assessed following every 3 treatment cycles until treatment discontinuation.

Time frame: From randomization to the first overall response, or death (up to approximately 34 months)

MDS Cohort: Kaplan-Meier Estimate of Time to AML Transformation

Participants were monitored for transformation to acute myeloid leukemia (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 date the participant had documented transformation to AML (up to approximately 34 months)

MDS Cohort: Percentage of Participants With Disease Transformation to AML

Disease transformation to acute myeloid leukemia (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. Participants with no transformation to AML were censored at the date of their last disease assessment.

Time frame: From randomization until death, lost to follow-up, withdrawal of consent for further data collection, or the end of the trial (up to approximately 34 months)

AML Cohort: Kaplan Meier Estimate of Time to First Response

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 the modified International Working Group (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. Response was assessed following every 3 treatment cycles until treatment discontinuation.

Time frame: From randomization and the earliest date any response (up to approximately 34 months)

AML Cohort: Kaplan Meier Estimate of Relapse-free Survival

Relapse-free survival is defined as time from the date of first documented response (morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi)) to the date of disease relapse or death from any cause, whichever occurred first based on the modified International Working Group (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 date of disease relapse or death from any cause, whichever occurred first (up to approximately 34 months)

AML Cohort: Percentage of Participants Who Achieved a Complete Cytogenetic Response

Complete cytogenetic response (CyCR) based on the modified International Working Group (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). Response was assessed following every 3 treatment cycles until treatment discontinuation.

Time frame: From randomization up to approximately 34 months)

AML Cohort: Percentage of Participants With Hematologic Improvement

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. Response was assessed following every 3 treatment cycles until treatment discontinuation.

Time frame: From randomization up to approximately 34 months

AML Cohort: Kaplan-Meier Estimate of Duration of Response

Duration of response is defined as the time from the first response morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (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. Response was assessed following every 3 treatment cycles until treatment discontinuation.

Time frame: From randomization until relapse, PD, or death (up to approximately 34 months)

Number of Participants With Treatment-emergent Adverse Events (TEAEs)

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: From first dose to 90 days after last dose of durvalumab or 28 days after last dose of azacitidine proir to the extension study (up to approximately 34 months)

Kaplan-Meier Estimate of Overall Survival

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 date of death or last known alive date (up to approximately 34 months)

One-year Survival

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: At 12 months after randomization

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

Change From Baseline in Selected Hematology Parameters I

Baseline values are defined as the last assessment of a particular parameter prior to administration of the participants first dose.