Clinical Trials /

Venetoclax and Decitabine Assessment in Patients (≥60 - <75 Years) With Newly Diagnosed AML Eligible for Allo-SCT

NCT04476199

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Acute Myeloid Leukemia Arising from Previous Myelodysplastic Syndrome
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax and Decitabine Assessment in Patients (≥60 - <75 Years) With Newly Diagnosed AML Eligible for Allo-SCT
  • Official Title: Phase II Study on Venetoclax (VEN) Plus Decitabine (DEC) (VEN-DEC) for Elderly (≥60 <75years) Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) Elegible for Allogeneic Stem Cell Transplantation (Allo-SCT)

Clinical Trial IDs

  • ORG STUDY ID: GITMO-VEN-DEC
  • NCT ID: NCT04476199

Conditions

  • Acute Myeloid Leukemia

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment with VEN-DECExperimentalVenetoclax will be given with a 3-day ramp up beginning with 100 mg dose on Day 1, with 200mg on Day 2, 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.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  • Patients >60 <75 years of age
    
                   -  Diagnosis of AML eligible for allo-SCT from any donor
    
                   -  High- and Intermediate-Risk ELN
    
                   -  WBC <25x109/L (Hydroxyurea is permitted to meet this criterion)
    
                   -  adequate hepatic function (bilirubin ≤2 UNL; ALT/AST ≤2,5 UNL)
    
                   -  adequate renal function (creatinine clearance ≥50 ml/min)
    
                   -  ECOG Performance Status < 2
    
                   -  Males enrolled in the study with partners who are women of childbearing
                      potential, must be willing to use an acceptable barrier contraceptive method
                      during the trial.
    
                   -  Women of childbearing potential must use highly effective contraception for at
                      least 1 month after the last dose of VEN and for however long the EU SmPC says
                      for DEC
    
                   -  Willing and able to comply with all of the requirements and visits in the
                      protocol.
    
                   -  Written and signed informed consent.
    
            Exclusion Criteria:
    
              -  • Previous treatment for AML (Hydroxyurea is allowed) or for an antecedent
                 Myelodysplastic Syndrome (MDS).
    
                   -  Absence of informed consent
    
                   -  AML patients with t(15;17); t(8;21); inv(16)
    
                   -  Subject has known active CNS involvement with AML.
    
                   -  Low Risk ELN
    
                   -  grade >2 NCI-CTCAE (v. 5) adverse events at the time of enrollment
    
                   -  Serious organ dysfunction: left ventricular ejection fraction < 40%, FEV1, FVC,
                      DLCO (diffusion capacity) <40% of predicted, LFT > 5 times the upper limit of
                      normal, or creatinine clearance < 40 ml/min.
    
                   -  The evidence of HBV or HCV active infection (HBV DNA HCV RNA positive test).
    
                   -  Patients with HIV infection
    
                   -  Current uncontrolled infections
    
                   -  Patients with other life-threatening concurrent disease
    
                   -  Subjects with known hypersensitivity to any of the component medication
    
                   -  Subject has a history of other malignancies within 2 years prior to study entry,
                      with the exception of:
    
              -  Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of
                 breast;
    
              -  Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
    
              -  Previous malignancy confined and surgically resected (or treated with other
                 modalities) with curative intent. • Participation in another clinical trial within 1
                 month before the start of this trial
          
    Maximum Eligible Age:75 Years
    Minimum Eligible Age:60 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Response to VEN-DEC chemo-free combination (ELN Guidelines)
    Time Frame:At the end of cycle 2 (each cycle is 28 days)
    Safety Issue:
    Description:response to VEN-DEC induction will be assessed on bone marrow according to the ELN Guidelines (13), as following: - CR without minimal residual disease (CR-MRD neg); (Complete Remission ) bone marrow blasts 5%) - CR remission with incomplete hematologic recovery (CRi): Morphologic Leukemia-free State (MLFS) Partial Remission (PR): All hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%; - Primary refractory disease/Non response (NR): No CR or CRi after 2 courses of VEN-DEC; excluding patients with death in aplasia or death due to indeterminate cause;

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Gruppo Italiano Trapianto di Midollo Osseo

    Trial Keywords

    • Acute Myeloid Leukemia
    • Allogenic Stem Cell Transplant

    Last Updated

    July 14, 2020