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

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ClinicalTrials.gov Identifier: NCT03454984
Recruitment Status : Unknown
Verified February 2018 by Groupe Francophone des Myelodysplasies.
Recruitment status was:  Not yet recruiting
First Posted : March 6, 2018
Last Update Posted : November 15, 2018
Information provided by (Responsible Party):
Groupe Francophone des Myelodysplasies

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes Acute Myeloid Leukemia Drug: Guadecitabine Phase 2

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%.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: all patients eligible to receive SGI-110 at day 40 to day130 after transplantation, will be treated
Masking: None (Open Label)
Primary Purpose: Prevention
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
Estimated Study Start Date : November 2018
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : March 2022

Arm Intervention/treatment
Experimental: SGI-110
  • SGI 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
Drug: Guadecitabine
30/m2/day SubCutaneous for 5 days (Cycle = 28 days). total of 10 cycles
Other Name: SGI-110

Primary Outcome Measures :
  1. DFS [ Time Frame: 1 year post transplant ]
    Disease Free Survival at 1 year post transplant

Secondary Outcome Measures :
  1. Overall survival [ Time Frame: 1 year and 2 years ]
    Overall survival from the date of transplantation and from the date of inclusion

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03454984

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Contact: Fatiha Chermat 33171207059 fatiha.chermat-ext@aphp.fr

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CHU d'Angers
Angers, France, 49933
Contact: Sylvain THEPOT, md    33241354466    sylvain.thepot@chu-angers.fr   
Principal Investigator: Sylvain THEPOT, md         
CHU Estaing
Clermont-Ferrand, France, 63000
Contact: Benoit DE RENZIS, MD    33473750065    bderenzis@chu-clermontferrand.fr   
Principal Investigator: Benoit DE RENZIS, MD         
Hôpital St Vincent de Paul
Lille, France, 59020
Contact: Christian ROSE, prof    33320874532    Rose.Christian@ghicl.net   
Principal Investigator: Christian ROSE, prof         
CHU Nantes
Nantes, France, 44093
Contact: Pierre PETERLIN, MD    33240083333    pierre.peterlin@chu-nantes.fr   
Principal Investigator: Pierre PETERLIN, MD         
Hôpital Archet 1
Nice, France, 06200
Contact: Thomas CLUZEAU, Prof    33492035844    cluzeau.t@chu-nice.fr   
Hôpital St Louis
Paris, France, 75010
Contact: Marie Robin, MD    33142499660    marie.robin@aphp.fr   
Principal Investigator: Marie Robin, MD         
Hôpital Pitié-Salpêtrière
Paris, France, 75013
Hôpital Necker
Paris, France, 75743
Contact: Felipe SUAREZ, MD    33144495368    felipe.suarez@aphp.fr   
Principal Investigator: Felipe SUAREZ, MD         
CHU de Haut-Lévèque
Pessac, France, 33604
Contact: Sophie DIMICOLI-SALAZAR, md    33557656511    sophie.dimicoli-salazar@chu-bordeaux.fr   
Principal Investigator: Sophie DIMICOLI-SALAZAR, MD         
Centre Hospitalier Lyon-Sud
Pierre-Bénite, France, 69495
Contact: Eric WATTEL, Prof    33478862205    eric.wattel@chu-lyon.fr   
Principal Investigator: Eric WATTEL, Prof         
CHU Toulouse - IUCT Oncopole
Toulouse, France, 31059
Contact: Odile BEYNE-RAUZY, Prof    33531156248    beynerauzy.odile@iuct-oncopole.fr   
Principal Investigator: Odile BEYNE-RAUZY, Prof         
CHU Brabois
Vandœuvre-lès-Nancy, France, 54511
Contact: Agnes GUERCI-BRESLER, md    33383153281    a.guerci@chru-nancy.fr   
Principal Investigator: Agnes GUERCI-BRESLER, md         
Sponsors and Collaborators
Groupe Francophone des Myelodysplasies
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Principal Investigator: Marie Robin, MD Hôpital Saint Louis
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Responsible Party: Groupe Francophone des Myelodysplasies
ClinicalTrials.gov Identifier: NCT03454984    
Other Study ID Numbers: GFM-GUA-DLI
First Posted: March 6, 2018    Key Record Dates
Last Update Posted: November 15, 2018
Last Verified: February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Myelodysplastic Syndromes
Bone Marrow Diseases
Hematologic Diseases
Antineoplastic Agents