A Study of Safety, Efficacy and Pharmacodynamics of Azacitidine in Children and Young Adults With Acute Myeloid Leukemia.
Condition: Leukemia, Myeloid, Acute
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Study type: Interventional
Phase: Phase 2

Summary: 
      This study is a randomized, multicenter, open-label, Phase 2 study that will be run in 2
      parts: a safety run-in part to determine the dose of azacitidine and then a second part to
      determine the efficacy of that dose in children and young adults with acute myeloid leukemia
      in molecular relapse after their first complete remission.

      Indication Treatment of children and young adults with molecular relapse of acute myeloid
      leukemia (AML) after first complete remission (CR1).

      Objectives Primary Objectives Safety Run-in Part To establish a safe and tolerable dose of
      azacitidine to be used in the randomized part of the study.

      Randomized Part To evaluate the effect of azacitidine treatment in AML subjects at molecular
      relapse after CR1 when compared to no treatment with regard to the progression-free rate
      (PFR) at Day 84 (±4 days) post randomization.

      Secondary Objectives Safety Run-in Part To establish azacitidine plasma pharmacokinetic (PK)
      parameters in subjects with molecular relapse AML after CR1 and to assess efficacy.

      Randomized Part To evaluate the safety, pharmacodynamics (PD), and efficacy of azacitidine
      treatment in subjects with molecular relapse AML after CR1.

      Study Design The population of this trial consists of children and young adults with AML who
      achieved a complete response (CR) with molecular remission, defined as Minimal Residual
      Disease (MRD) less than 5 x 10-4, following their initial induction therapy and who
      subsequently have a molecular relapse (defined as increase in MRD level by at least 1 log
      [10-fold] to a level greater than or equal to 5 x 10-4 despite a normal percentage [<5%] of
      myeloblasts in the bone marrow [BM] aspirate and peripheral blood [PB], and in the absence of
      proven histological extramedullary relapse). Eligible subjects have a documented diagnosis of
      AML with at least one of the following molecular aberrations t(8;21), RUNX1-RUNX1T1, inv(16),
      CBFb/MYH11, t(9;11), MLL-AF9, NPM1 mutation, or FLT3-ITD mutation. Enrolled/randomized
      pediatric subjects will be followed with regular MRD testing in order to detect a molecular
      relapse.

      In the safety run-in part, up to 12 subjects aged 3 months to less than 18 years will be
      enrolled. Six subjects will be enrolled in the first cohort of 100 mg/m2 azacitidine
      administered intravenously (IV) on Days 1 to 7 of a 28-day cycle. Six additional subjects
      could be enrolled into a second cohort of 75 mg/m2 azacitidine administered IV on Days 1 to 7
      of a 28-day cycle depending on the safety and tolerability results of the 100 mg/m2 cohort.

      In the randomized part of the study at least 68 subjects will be randomized (or more
      depending on whether at least 64 subjects are evaluable for the primary endpoint), with at
      least 60 of the subjects being less than 18 years of age.

      Both parts of the study, the safety run-in part and the randomized part, will contain 3
      periods: the screening period, the treatment period and the follow-up period. The screening
      period will last no more than 10 days in the safety run-in part after which the subjects may
      be enrolled and treated. In the randomized part, the screening period will last an indefinite
      amount of time until detection of a molecular relapse in the PB followed by confirmation of
      the relapse in both PB and BM aspirate, at which point the subject may then be randomized.
      Subjects will be treated with azacitidine (safety run-in part) or in accordance to their
      assigned treatment arm (randomized part). Upon discontinuation from the treatment period,
      subjects will enter into the follow-up period which will last up to 2 years from last patient
      enrolled/randomized.
    

Detailed description: 
      Study Population Subjects with AML in molecular relapse after CR1, aged 3 months to less than
      18 years of age for the safety run-in part, and 3 months to less than 21 years of age for the
      randomized part.

      Length of Study Study duration is estimated to last up to approximately 9 years from the time
      of the first subject enrollment until completion of the follow-up period for all subjects
      enrolled/randomized. Estimated duration is based on expected duration of the study
      treatment/'watch and wait' period (3 months) and completion of the follow-up period (2 years
      from randomization of last subject).

      The End of Trial is defined as either the date of the last visit of the last subject to
      complete the study, or the date of receipt of the last data point from the last subject that
      is required for primary, secondary and/or exploratory analysis, as pre-specified in the
      protocol and/or the Statistical Analysis Plan, whichever is the later date.

      Study Treatments Safety Run-in Part Intravenous azacitidine 100 mg/m2 with a possible
      decrease to a cohort of 75 mg/m2, Days 1 to 7 of a 28-day cycle for a maximum of 3 cycles.

      Randomized Part Intravenous azacitidine dose established during the safety run-in part on
      Days 1 to 7 of a 28-day cycle for a maximum of 3 cycles (for subjects randomized to the
      azacitidine arm).

      Overview of Efficacy Assessments The primary endpoint of the randomized part, PFR at Day 84
      (±4 days) post randomization, will be assessed at Day 80 to 88 (approximately end of Cycle 3
      of active treatment) post randomization for both the control and the experimental arm. In
      case of clinical relapse, the investigator will be asked to document it and to evaluate the
      morphology and immunophenotyping in BM aspirate and PB. This must be done according to
      standardized diagnostic procedures contained in the AML BFM 2012 guidelines (Creutzig, 2012).

      Overview of Safety Assessments Subject safety will be assessed at each visit during the
      study. Any AE will be reported and recorded in an AE electronic case report form (eCRF). For
      serious adverse events (SAEs) an expedited reporting procedure will be used in addition to an
      AE eCRF. The rate of AEs and SAEs, including second malignancies and cardiovascular events
      which are events of special interest for this study, and abnormal laboratory values and vital
      signs (NCI CTC Criteria version 4.0 to be used to grade AEs) will be collected while the
      subject is on study therapy and during the 'watch and wait' period. Once the subject starts
      the next-line therapy or has a HSCT, only SAEs related to study treatment (experimental arm)
      or HSCT will be collected for the safety analysis.

      Overview of Statistical Methods Subjects from both the safety run-in part and randomization
      part shall be used for analysis of the safety and efficacy endpoints which are common to both
      parts of the study. In addition, a PK analysis will be performed on subjects from the safety
      run-in part, and analysis of the PFR endpoint and all other endpoints unique to the
      randomized part will only be performed on randomized subjects.

      One interim analysis for futility of the primary endpoint is planned during the randomization
      part of the study once the first 32 (50% of 64) randomized subjects become evaluable for the
      primaryendpoint analysis. The study will be stopped if the criteria for futility is met.

      Subject demographic and baseline characteristics, disposition, and safety data will be
      presented by study part as well as treatment dose (safety run-in part) and study arm
      (randomized part) as well as in aggregate for all subjects receiving azacitidine regardless
      of study part. All efficacy based endpoints will be presented by treatment arm.

      First data analysis and reporting of the safety run-in part will be conducted once the final
      dose assessment SMC meeting has been held (final safety run-in SMC date = data cut-off of
      initial analysis of safety run-in part). This analysis will consist of the safety run-in
      primary endpoint and the PK secondary endpoint only. All other safety run-in part secondary
      endpoints will be analyzed at the time of analysis and reporting of data from the randomized
      part.

      In addition to PK data analysis, all other secondary endpoints can only be analyzed and
      reported as and when required based on subjects who have had at least 6 months from
      enrollment (safety run-in part) or randomization (randomization part).
    

Intervention name(s): Azacitidine; Control Arm
Intervention type(s): Drug; Other
Intervention MeSH terms: Azacitidine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Children; Young Adults; Azacitidine; Acute Myeloid Leukemia; Molecular Relapse; Vidaza; AZA-AML-004