Venetoclax and Decitabine Assessment in Patients (≥60 - <75 Years) With Newly Diagnosed AML Eligible for Allo-SCT
Condition: Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Study type: Interventional
Phase: Phase 2

Summary: 
      This trial is a no profit, prospective, phase II, multicentre, non-randomised, uncontrolled,
      single group assignment, open label study to evaluate the safety and efficacy of the
      "chemo-free" combination Venetoclax plus Decitabine (VEN-DEC) as "bridge" to allo-SCT in
      elderly (≥ 60 - < 75 years) AML patients. The primary objective is to evaluate the proportion
      of elderly (≥60 - <75 years) patients with newly diagnosed AML, eligible for allo-SCT,
      treated with the "chemo-free" combination Venetoclax plus Decitabine (VEN-DEC) who get
      allo-SCT in CR/Cri/MLFS.
    

Detailed description: 
      This trial is a no profit, prospective, phase II, multicentre, non-randomised, uncontrolled,
      single group assignment, open label study to evaluate the proportion of elderly (≥60 - <75
      years) patients with newly diagnosed AML, eligible for allo-SCT, treated with the
      "chemo-free" combination Venetoclax plus Decitabine (VEN-DEC) who get allo-SCT in
      CR/CRi/MLFS, organized under the auspices of the Gruppo Italiano TRapianti di Midollo Osseo
      (GITMO) that involves the prinicipla centres active in transplantation of any kind of stem
      cells in Italy. The target for this study is 100 patients.

      Biologic characterization of AML will be performed at each participating Center by flow
      cytometry, cytogenetics and RT-qPCR on target genes (FLT3, NPM1A, WT1,) at disease onset. MRD
      monitoring will be performed at each participating Center by flow cytometry, cytogenetics and
      RT-qPCR (routine assessment) at the time of CR/CRi/MLFS before allo-SCT and during follow up
      (at least 4 timepoints: +100 days, +180 days, +1 year and +2 years from allo-SCT).

      Genomic analysis by NGS gene-panel (Sophia Genetics) exploring the mutational status of the
      genes involved in of AML will be centralized in Brescia Laboratory at the enrollment into the
      study (diagnosis) and at the time of no response (PR/NR), before allo-SCT in patients in
      CR/CRi/MLFS and in case of relapse, at any time.

      Primary Objectives To evaluate the proportion of elderly (≥60 - <75 years) patients with
      newly diagnosed AML eligible for allo-SCT treated with the "chemo-free" combination
      Venetoclax plus Decitabine (VEN-DEC) who get allo-SCT in CR/CRi/MLFS.

      Secondary Objectives

        -  Incidence and severity of adverse drug reactions (ADR) classified by System Organ Class
           (SOC) and preferred term (PT) from start treatment with Ventoclax and Decitabine to
           allo-SCT

        -  Efficacy of VEN-DEC combination

        -  Evaluation of the outcome of allo-SCT in term of:1) Incidence of graft failure at day
           +30, +100 from allo-SCT2) Incidence of Non-Relapse Mortality (NRM) at day +100, 1 year
           and 2 years from allo-SCT3) Incidence and severity of acute GVHD at day +100 from
           allo-SCT4) Incidence and severity of chronic GVHD at 1 year and 2 years from allo-SCT5)
           Probability of GRFS (GVHD free, relapse free survival) at 1 and 2 years from allo-SCT

        -  Relapse incidence (RI) at 1 year and 2 years from allo-SCT

        -  Disease-free survival (DFS) at 1 and 2 years from allo-SCT

        -  Overall Survival (OS) at 1 and 2 years from allo-SCT

        -  Correlation of immunophenothype, cytogenetic, molecular and NGS-genomic profiles with
           sensitivity (CR - CRi - MLFS) or resistance (PR/NR) to "chemo-free" combination
           Venetoclax plus Decitabine (VEN-DEC)

        -  Correlation of immunophenothype, cytogenetic, molecular and NGS-genomic profiles with
           the outcome of allo-SCT in terms of NRM, probability of RI, DFS, OS.

      This study has 2 endpoints

      Primary Endpoint Proportion of elderly (≥60 - <75 years) patients with newly diagnosed AML
      eligible for allo-SCT treated with the "chemo-free" combination Venetoclax plus Decitabine
      (VEN-DEC) who get allo-SCT in CR/CRi/MLFS.

      Secondary Endpoints

        -  Efficacy of VEN-DEC combination

        -  Cumulative incidence of graft failure at +30 days, +100 days from transplant

        -  Outcome of allo-SCT in term of NRM at day +100, 1 year and 2 years from allo-SCT

        -  Cumulative incidence and severity of acute GvHD at 100 days after transplant

        -  Cumulative incidence and severity of chronic GvHD at 1 and 2 years post transplant

        -  RI at 1 and 2 year after transplantation from days of transplant.

        -  OS at 1 and 2 years post transplant

        -  DFS at 1 and 2 years post transplant

        -  1 and 2 year probability of GRFS

        -  Correlation of immunophenothype, cytogenetic, molecular and NGS-genomic profiles with
           sensitivity (CR - CRi - MLFS) or resistance (PR-NR) to "chemo-free" combination
           Venetoclax plus Decitabine (VEN-DEC)

        -  Correlation of immunophenothype, cytogenetic, molecular and NGS-genomic profiles with
           the outcomes of allo-SCT: NRM, RI, DFS, OS.

      Biologic characterization of AML will be performed at each participating Center by flow
      cytometry, cytogenetics and RT-qPCR on target genes (FLT3, NPM1A, WT1,…) at disease onset.
      MRD monitoring will be performed at each participating Center by flow cytometry, cytogenetics
      and RT-qPCR (routine assessment) at the time of CR/CRi/MLFS, before allo-SCT and during
      follow up (at least 4 timepoints: +100 days, +180 days, +1 year and +2 years from
      allo-SCT).Genomic analysis by NGS gene-panel (Sophia Genetics) exploring the mutational
      status of the genes involved in of AML will be centralized in Brescia Laboratory at the
      enrollment into the study (diagnosis) and at the time of no response (PR/NR), before allo-SCT
      in patients in CR/CRi/MLFS and in case of relapse, at any time.

      Venetoclax will be given with a 3-day ramp up beginning with 100 mg dose on Day 1 to reach
      the final dose of 400 mg on Day 3 of Cycle 1. Venetoclax will be continued at 400 mg daily.
      Tumor lysis prophylaxis will be administered from day -4, cycle 1 (oral uric acid reducing
      agent and hydration with at least 1.5 L/day).

      Decitabine will be administered at the dose of 20 mg/sqm intravenously from day 1 to day 5
      every 28 days (VEN-DEC) for 2 cycles. The response will be assessed after the 2nd Cycle
      VEN-DEC according to ELN criteria. In case of CR/CRi/MLFS, patients will undergo allo-SCT
      within 2 months. A maximum of two additional VEN-DEC cycles is permitted while waiting for
      allo-SCT. In case of NR or PR after the 2nd Cycle VEN-DEC, two additional cycles of VEN-DEC
      will be administered and patients achieving CR/CRi/MLFS will undergo allo-SCT as soon as
      possible (within 2 months). Patients with NR or PR will be treated according to single center
      policy, including also allo-SCT.

      Patients achieving Morphologic Leukemia-free State (MLFS) will be considered responsive
      patients, since the percentage of BM blast cells is < 5%. These patients may undergo allo-SCT
      after 2 - 4 cycles of VEN-DEC.Granulocyte colony stimulating factor (G-CSF) will be allowed
      during VEN-DEC in case of febrile neutropenia. Whenever clinically indicated, G-CSF use has
      to be notified tin the CRF.

      Population for analysis The population for analysis in this trial will be the Intent to Treat
      (ITT) population. All patients who have received at least one therapeutic dose of study
      medications will be included in the ITT analysis.

      Sample size calculation The study is designed as a Simon optimal two-Stage Phase II clinical
      trial, including a planned futility check: after enrollment of the first 30 patients the
      Investigator will pause for the futility check is at that time point the target 4 patients
      will not yet be admitted to allo-SCT. Based on the current literature, less than 10% of
      elderly (>60 <75 years) AML patients can be submitted to allo-SCT, due to no-response to
      induction conventional chemotherapy (NR or PR) and /or to treatment toxicity. Therefore, to
      test the null hypothesis (conventional chemotherapy) that p ≤0.10 versus the alternative
      (VEN-DEC) that p ≥0.20, the expected sample size is 89 patients, with a probability of early
      termination of 0.647, when true proportion is 0.1. Alpha error is 0.0478 and beta value
      0.1982. If there are 3 or fewer patients submitted to allo-SCT in the first 30 enrolled
      patients, the trial will be terminated for futility. Otherwise, considering an overall 12% of
      drop-out rate, 70 additional patients will be accrued for a total of 100 patients: in the
      second stage 70 patients will only be enrolled if at least 4 patients of the first stage
      undergo allo-SCT. The null hypothesis will be rejected if 14 of more patients treated with
      VEN-DEC will be submitted to allo-SCT in CR/CRi/MLFS.

      The study is considered completed when the 100th patient will be enrolled. It is planned to
      complete the total enrollment (100 patients) in 18 months, starting from the first patient
      enrolled.

      The follow-up according to the protocol is 2 years for each patient from the day of
      enrollment. In the transplanted patients the pre-transplant period will be followed by 2
      years post-transplant follow-up

      The study will be performed in 4 years from the first patient enrolled according to the
      following times:

      18 moths for enrollment (from the first patient) and for database completion and cleaning 24
      months of follow up. In the transplanted patients the pre-transplant period will be followed
      by 2 years post-transplant follow-up 6 months for statistical analysis, drafting of the final
      report and paper.

      The study will be conducted in accordance with the ethical principles derived from the
      Declaration of Helsinki, the CGP and regulations.

      Before starting the study, the protocol will be sent to the Ethics Committee, in accordance
      with the current legislation on interventional study.

      The protocol has been written and the study will be conducted according to the International
      Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
      Harmonized tripartite Guideline for GCP, issued by European Union. IRB approval must be
      obtained prior to the starting of the trial. ICF must be submitted to appropriate authority
      or IRB together with clinical protocol for written approval.
    

Intervention name(s): Venetoclax and Decitabine
Intervention type(s): Combination Product
Intervention description(s): The prognosis of acute myeloid leukemia (AML) patients aged over 60 years is poor and allogeneic stem cell transplantation (allo-SCT) is the only curative option.The association VEN-DEC is a promising combination therapy for AML elderly patients who are fit and eligible for allo-SCT.
Intervention MeSH terms: Venetoclax; Decitabine
Intervention model: Single Group Assignment
Intervention model description: These patients may undergo allo-SCT after 2 - 4 cycles of VEN-DEC
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Acute Myeloid Leukemia; Allogenic Stem Cell Transplant