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

NCT02775903

Description:

This is a Phase 2, multicenter, randomized, parallel-group, open-label study consisting of 3 phases: Screening, Treatment, and Follow-up. To confirm the safety, ie, the absence of overlapping toxicities of the combination treatment regimen, an early safety monitoring will be performed based on approximately the first 12 subjects randomized. A total of approximately 72 subjects will be included in the Myelodysplastic syndromes (MDS) cohort and approximately 110 subjects in the Acute Myeloid Leukemia (AML) cohort.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: MEDI4736-MDS-001
  • NCT ID: NCT02775903

Conditions

  • Leukemia, Myeloid, Acute
  • Myelodysplastic Syndromes

Interventions

DrugSynonymsArms
AzacitidineAzacitidine in combination with Durvalumab
DurvalumabMEDI4736Azacitidine in combination with Durvalumab

Purpose

This is a Phase 2, multicenter, randomized, parallel-group, open-label study consisting of 3 phases: Screening, Treatment, and Follow-up. To confirm the safety, ie, the absence of overlapping toxicities of the combination treatment regimen, an early safety monitoring will be performed based on approximately the first 12 subjects randomized. A total of approximately 72 subjects will be included in the Myelodysplastic syndromes (MDS) cohort and approximately 110 subjects in the Acute Myeloid Leukemia (AML) cohort.

Detailed Description

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

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

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

Trial Arms

NameTypeDescriptionInterventions
Azacitidine in combination with DurvalumabExperimentalSubcutaneous azacitidine (75 mg/m2 for 7 days Q4W) in combination with IV durvalumab at a dose of 1500 mg on Day1 Every 4 weeks (Q4W)
  • Azacitidine
  • Durvalumab
Azacitidine aloneActive ComparatorSubcutaneous azacitidine alone at the dose of 75 mg/m2 for 7 days Every 4 weeks (Q4W)
  • Azacitidine

Eligibility Criteria

        Inclusion Criteria:

          -  For both cohorts:

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

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

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

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

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

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

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

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

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

               1. has achieved menarche at some point

               2. has not undergone a hysterectomy or bilateral oophorectomy or

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

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

             4. Male subject must:

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

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

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

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

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

                  MDS Cohort:

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

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

                  Acute myeloid leukemia (AML) Cohort:

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

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

                    -  AML secondary to prior MDS, or

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

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

                  Exclusion Criteria:

          -  For both cohorts:

               1. Prior hematopoietic stem cell transplant.

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

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

               4. Inaspirable bone marrow.

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

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

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

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

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

                    -  Basal or squamous cell carcinoma of the skin

                    -  Carcinoma in situ of the cervix

                    -  Carcinoma in situ of the breast

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

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

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

                    -  Subjects with vitiligo or alopecia;

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

                    -  Subjects with psoriasis not requiring systemic treatment

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

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

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

                    -  Significant cardiac arrhythmia

                    -  Myocardial infarction

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

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

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

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

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

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

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

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

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

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

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

              18. History of primary immunodeficiency.

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

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

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

              22. Presence of advanced malignant hepatic tumors.

              23. Any of the following laboratory abnormalities:

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

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

                    -  Serum creatinine > 2.5 × ULN.

                  MDS Cohort:

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

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

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

              27. Absolute WBC count ≥ 15 × 109/L.

                  AML Cohort:

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

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

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

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

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

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

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

              35. Known history or presence of Sweet Syndrome at screening
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate (ORR)- MDS(Myelodysplastic syndromes)
Time Frame:Up to approximately 6 Months
Safety Issue:
Description:Is defined as percent of subjects with Complete Response (CR), marrow complete remission (mCR), Partial remission (PR), and/or Hematological improvement (HI) as determined using the IWG 2006 response criteria

Secondary Outcome Measures

Measure:Time to response - MDS
Time Frame:Up to approximately 6 months
Safety Issue:
Description:Is defined as time from randomization to first documented response according to IWG 2006 response criteria.
Measure:Relapse-free survival - MDS
Time Frame:Up to approximately 12 months
Safety Issue:
Description:Is defined as time from the date CR, PR or mCR is first documented until the date of documented relapse, death from any cause, or lost to follow-up, whichever occurs first according to IWG 2006 response criteria.
Measure:Cytogenetic response - MDS
Time Frame:Up to approximately 12 months
Safety Issue:
Description:Is defined as proportion of subjects achieving complete cytogenetic response or partial cytogenetic response according to IWG 2006 response criteria
Measure:Progression-free survival (PFS) - MDS
Time Frame:Up to approximately 12 months
Safety Issue:
Description:Is defined as time from randomization to the first documented Progressive disease (PD) or death due to any cause, whichever occurs first.
Measure:Duration of hematologic response- MDS
Time Frame:Up to approximately 12 months
Safety Issue:
Description:Is defined as the time from the date response/improvement is first observed until the date the subject has a subsequently documented relapse or disease progression as defined by the IWG 2006 response criteria
Measure:Time to AML transformation- MDS
Time Frame:Up to approximately 12 months
Safety Issue:
Description:Is defined as the time from randomization until the date the subject has transformation to AML
Measure:Transformation to AML- MDS
Time Frame:Up to approximately 12 months
Safety Issue:
Description:Is defined as proportion of subjects having transformation to AML
Measure:Time to response - AML
Time Frame:Up to approximately 6 months
Safety Issue:
Description:Is defined as time from randomization to first documented response based on modified IWG 2003 response criteria
Measure:Relapse-free survival- AML
Time Frame:Up to approximately 12 months
Safety Issue:
Description:Is defined only for subjects who achieve Complete remission (CR) or Complete remission with incomplete blood recovery (CRi) and is measured as the interval from the date of first documented CR or CRi to the date of documented relapse, death from any cause, or lost to follow-up, whichever occurs first
Measure:Complete cytogenetic response (CyCR)- AML
Time Frame:Up to approximately 12 months
Safety Issue:
Description:Is defined as proportion of subjects with complete cytogenetic response (CyCR) based on modified IWG 2003 response criteria
Measure:Hematologic Improvement Rate - AML
Time Frame:Up to approximately 12 months
Safety Issue:
Description:Is defined as rate of Hematological improvement - Neutrophil response (HI-NE) + Hematological improvement - Platelet response (HI-P) + Hematological improvement - Erythroid response (HI-E) according to IWG 2006 response criteria
Measure:Duration of response - AML
Time Frame:Up to approximately 12 months
Safety Issue:
Description:Is defined as the time from the first documented CR/CRi to documented morphologic relapse, PD based on modified IWG 2003 response criteria for AML, or death due to any cause, whichever occurs first.
Measure:Adverse Events (AEs) - MDS + AML
Time Frame:Up to approximately 15 months
Safety Issue:
Description:Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA). Adverse event listings will include the verbatim term and the MedDRA preferred term. Adverse events will be graded according to CTCAE Version 4.03 criteria
Measure:Overall survival - MDS + AML
Time Frame:Up to approximately 24 months
Safety Issue:
Description:Is defined as time from randomization to death due to any cause.
Measure:One-year survival
Time Frame:Up to approximately 12 months
Safety Issue:
Description:Is defined as the probability of survival at 1 year from randomization
Measure:Pharmacokinetics- Cmax
Time Frame:Up to approximately 231 days
Safety Issue:
Description:Maximum observed concentration
Measure:Pharmacokinetics- AUC
Time Frame:Up to approximately 231 days
Safety Issue:
Description:Area under the concentration-time curve
Measure:Pharmacokinetics- Tmax
Time Frame:Up to approximately 231 days
Safety Issue:
Description:Time to maximum concentration
Measure:Pharmacokinetics- t1/2
Time Frame:Up to approximately 231 days
Safety Issue:
Description:Terminal elimination half-life
Measure:Pharmacokinetics- CL/F
Time Frame:Up to approximately 231 days
Safety Issue:
Description:Clearance of distribution
Measure:Pharmacokinetics- Vz/F
Time Frame:Up to approximately 231 days
Safety Issue:
Description:Volume of distribution

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Celgene

Trial Keywords

  • MEDI4736
  • Durvalumab
  • Myelodysplastic Syndromes
  • Acute Myeloid Leukemia
  • Hematopoietic Stem Cell Transplantation
  • Azacitidine
  • Safety
  • Efficacy
  • PD-L1

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