Clinical Trials /

SGI-110 and Donor Lymphocyte Infusions (DLI) After Allogeneic Stem Cell Transplantation

NCT03454984

Description:

High risk MDS (Myelodysplastic Syndrome) patients will be treated with SGI-110 after Allogeneic Stem Cell Transplantation in the hypothesis that SGI-110 maintenance given early after HSCT can prevent relapse without increasing non-relapse mortality translating in an improved disease-free survival.

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

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: SGI-110 and Donor Lymphocyte Infusions (DLI) After Allogeneic Stem Cell Transplantation
  • Official Title: Guadecitabine SGI-110 and Donor Lymphocyte Infusions (Dli) After Allogeneic Stem Cell Transplantation (Allo Sct) in Very High Risk MDS or AML Patients

Clinical Trial IDs

  • ORG STUDY ID: GFM-GUA-DLI
  • NCT ID: NCT03454984

Conditions

  • Myelodysplastic Syndromes
  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
GuadecitabineSGI-110SGI-110

Purpose

High risk MDS (Myelodysplastic Syndrome) patients will be treated with SGI-110 after Allogeneic Stem Cell Transplantation in the hypothesis that SGI-110 maintenance given early after HSCT can prevent relapse without increasing non-relapse mortality translating in an improved disease-free survival.

Detailed Description

      Allogeneic stem cell transplant (HSCT) is the only curative treatment in patients with
      intermediate-2 and high risk patients (according to classical IPSS) but approximately 30% of
      patients relapse and 30% of patients die from non-relapse complications after HSCT. Risk
      factors for post-transplant outcome are related to the patient itself (age, comorbidity), the
      disease risk and transplant characteristics (higher relapse in patients receiving a reduced
      intensity conditioning regimen and in those receiving a T-cell depleted graft).

      The risk of post-transplant relapse is however particularly high (> 60-70%) in patients with
      very poor cytogenetics according to the revised IPSS, patients with monosomal karyotype, and
      patients with TP53 mutation. Taking into account that these patients also have non-relapse
      mortality, expected post-transplant survival is very poor, less than 15% and more often 10%.
      It has been reported that 30 to 35% of those high risk patients respond to hypomethylating
      agents (HMA) but they have very short remission duration, less than 5 months in median. A
      recent study reported a prospective, uncontrolled trial including 84 patients with MDS, AML
      patients receiving Decitabine (DAC). The authors highlight that the response was better in
      patients with unfavorable cytogenetics and that TP53 clones was cleared after treatment. The
      cytogenetics was no more a prognostic factor suggesting that DAC has improved survival
      especially in high-risk patients who had an 11.6-month median survival. This study suggests
      that DAC is particularly encouraging in high-risk patients. Guadecitabine (SGI-110) is a
      novel hypomethylating dinucleotide of Decitabine and deoxyguanosine resistant to degradation
      by cytidine deaminase. Safety and tolerance of SGI-110 in patients with MDS has been reported
      and this drug is now considered as a potential treatment in patients with AML or MDS. The
      concept of post-transplant maintenance therapy with one HMA in AML and MDS has been studies
      by several teams and there are 2 prospective trials exploring escalating dose in
      5-azacytidine (AZA) and DAC. a group has reported that DAC maintenance was safe and that
      there was no dose limiting toxicities with the highest dose tested at 15 mg/m2/day 5 days
      every 6 weeks from day 50 post-transplant. A phase II trial, the RICAZA study, has tested a
      maintenance HMA early after transplant from day 40. 37/51 pre-screened patients could receive
      AZA and only 10% experienced complications. Two-year OS was 50%. HMA induces leukemic
      differentiation and re-expression of tumor or viral associated genes that had been
      epigenetically silenced. At high dose, cell die from apoptosis triggered by DNA synthesis
      arrest and at low doses, cells survive but change their gene expression to favor
      differentiation. Several groups have demonstrated effects of HMA on T cell-mediated
      anti-tumor activity which might promote graft-versus-leukemia or MDS effect. In another hand,
      HMA have been reported to increase the frequency of Tregs after HSCT and lower acute GVHD
      which might lower non-relapse mortality. Regarding GVHD, acute GVHD should be prevented due
      to the higher non-relapse mortality associated with acute GVHD. In contrast, several studies
      have highlighted the benefit of chronic GVHD on relapse risk justifying immunotherapy, donor
      lymphocyte infusion (DLI) later after HSCT to prevent relapse. The therapeutic strategy
      combining pre-emptive HMA in combination with DLI has been tested in a prospective study, the
      RELAZA trial, based on CD34 chimerism.

      Taken together, these studies provide a rationale for the early administration of DMA, ie:
      SGI 110, associated with late DLI after HSCT for AML and MDS. The hypothesis is that SGI 110
      maintenance given early after HSCT can prevent relapse without increasing non-relapse
      mortality translating in an improved disease-free survival. This hypothesis will be tested in
      the higher risk patients, especially those with TP53 for whom relapse risk is higher than
      50%.
    

Trial Arms

NameTypeDescriptionInterventions
SGI-110ExperimentalSGI 110 (Guadecitabine) will start on day 40, In case the patient is not eligible yet, he should be assessed again each 30 days until day 130, after what, he is not considered eligible for a preventive treatment by SGI. Initial dose will be 30/m2/day SQ for 5 days total 10 cycles of SGI-110
  • Guadecitabine

Eligibility Criteria

        Inclusion Criteria:

          -  Patients aged from 18 to 70 years

          -  MDS or AML with unfavorable genetics defines as follow:

          -  4 cytogenetic abnormalities or more or

          -  3 cytogenetic abnormalities and TP53 or

          -  3 cytogenetic abnormalities and monosomal karyotype or

          -  Mutations involving EVI1

          -  Marrow blast < 20% for and non-proliferative disease

          -  AML patients should have received chemotherapy before transplant

          -  A donor is available (HLA matched or mismatched)

          -  Contraception in women < 50 years and for men at least the first six months after
             transplant and 3 months after the last dose of guadecitabine"

        Exclusion Criteria:

          -  Karnofsky less than 70%

          -  Cancer in less than 2 years before inclusion or cancer not in remission the last 2
             years before inclusion (except in situ cancer or baso cellular cancer)

          -  Cardiac failure with EF < 50%

          -  Creatininemia level > 150 µmol/L

          -  Liver enzyme > 3 N

          -  Conjugated bilirubinemia > 25 µmol/L

          -  MDS occurring in a patients with Fanconi anemia or congenital dyskeratosis

          -  Proliferative disease in patients no in remission: WBC> 15 G/L or use of continuous
             cytotoxic to maintain WBC < 15G/L

          -  Proliferative AML: hyperleucocytosis > 15 G/L, blast count higher than 10% or lower
             than 10% for less than 6 weeks

          -  No contraception

          -  Pregnant women or breastfeeding women
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:DFS
Time Frame:1 year post transplant
Safety Issue:
Description:Disease Free Survival at 1 year post transplant

Secondary Outcome Measures

Measure:Overall survival
Time Frame:1 year and 2 years
Safety Issue:
Description:Overall survival from the date of transplantation and from the date of inclusion

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Groupe Francophone des Myelodysplasies

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