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Trial record 1 of 1 for:    NCT02876679
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Cyclophosphamide Versus Anti-thymocyte Globulin for GVHD Prophylaxis After RIC Allo-SCT (ATG-CyGVHD)

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ClinicalTrials.gov Identifier: NCT02876679
Recruitment Status : Recruiting
First Posted : August 24, 2016
Last Update Posted : February 5, 2019
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE August 12, 2016
First Posted Date  ICMJE August 24, 2016
Last Update Posted Date February 5, 2019
Actual Study Start Date  ICMJE April 6, 2017
Estimated Primary Completion Date February 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 18, 2016)
Composite endpoint of GVHD-free, relapse-free survival (GRFS) [ Time Frame: 12 Months ]
Absence of grade 3-4 acute GVHD, chronic GVHD requiring systemic treatment, relapse, or death
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02876679 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 18, 2016)
  • Cumulative incidence of grade 2-4 and grade 3-4 severe acute GVHD [ Time Frame: 6 Months ]
    Acute GVHD grading should be performed by the revised Glucksberg criteria (Przepiorka et al., 1995). The time of onset of acute grades II-IV and III-IV acute GVHD will be recorded, as well as the maximum grade achieved
  • Cumulative incidence of non-relapse mortality within the first 12 months after transplantation. [ Time Frame: 12 Months ]
    Death without evidence of disease recurrence. Disease recurrence will be considered a competing event.
  • Disease-free survival [ Time Frame: 12 months ]
    Relapse-free survival : time from date of transplant to death or relapse, whichever comes first. The event for this endpoint is relapse or death. Patients alive and free from disease relapse will be censored at last follow-up
  • Overall survival. [ Time Frame: 12 months ]
    Overall survival : time interval between date of transplant and death from any cause or for surviving patients, to last follow-up. The event for this endpoint is death from any cause.
  • Quality of Life (QoL) with EORTC QLQ-C30 [ Time Frame: 12 Months ]
    Evaluation by the questionnaire EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30)
  • Quality of Life (QoL) with FACT-BMT [ Time Frame: 12 Months ]
    Evaluation by the questionnaire FACT-BMT (Functional Assessment of Cancer Therapy - Bone Marrow Transplant)
  • Immune recovery measurement [ Time Frame: 12 Months ]
    Immune recovery measurement: number of patients with complete immune recovery (T, B and dendritic cells subsets)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Cyclophosphamide Versus Anti-thymocyte Globulin for GVHD Prophylaxis After RIC Allo-SCT
Official Title  ICMJE Cyclophosphamide Versus Anti-thymocyte Globulin for GVHD Prophylaxis After RIC Allo-SCT
Brief Summary The study is designed as a two arm randomized Phase II, multicenter trial comparing cyclophosphamide to anti-thymocyte globulin for Graft-versus-Host Disease (GVHD) prophylaxis in patients with hematologic malignancies undergoing reduced intensity conditioning hematopoietic stem cell transplantation.
Detailed Description

Allogeneic stem cell transplantation (allo-SCT) is a well-established therapy for different hematologic malignancies. Reduced-intensity conditioning (RIC) regimens can decrease the rate of toxicity/mortality in elderly patients, or in patients with poor medical condition. GVHD prophylaxis remains a challenging task after allo-SCT. The Flu-ivBu combination is a widely used RIC regimen, endorsed by EMA since July 2014. ATG in combination with cyclosporine-A ±mycophenolate mofetil is the backbone for GVHD prophylaxis in this setting. ATG can prevent GVHD with a good efficacy, but at the cost of a higher toxicity and profound immunosuppression, calling for more effective therapies. The most widely used RIC regimen in France incorporates fludarabine (Flu), intermediate doses of IV-busulfan (Bu) and anti-thymocyte globulins (ATG). While the use of ATG can prevent severe acute and chronic GVHD after allogeneic peripheral blood stem cell (PBSC) transplantation from both HLA-identical sibling and unrelated donors, some data suggested that in-vivo T-cell depletion with ATG in the RIC setting may induce a higher risk of disease relapse. Also, ATG induces profound immune suppression and increase incidence of opportunistic infections, especially EBV-related complications (relative risk=4.9; 95% CI[ 1.1-21.0]; P=0.03).

On the other hand, high-dose post-transplantation cyclophosphamide (PTCy) was developed to facilitate HLA-haploidentical allo-SCT using unmanipulated bone marrow (BM) cells. PTCy was effective in preventing both acute and chronic GVHD given its capacity to preferentially eliminate allo-reactive T cells and preserve regulatory T cells, both of which impact allogeneic immune reactions. Subsequently, the efficacy of PTCy as sole GVHD prophylaxis after myeloablative conditioning when using BM was also shown. However, BM is not the preferred source of stem cells after RIC allo-SCT, and the potential efficacy of PTCy on preventing GVHD when using PBSCs (which is the most frequently used source of allogeneic cells worldwide) is debated.

The advent of PTCy therapy is nowadays on the cutting edge. Thus, the potential efficacy (and cost-effectiveness) of PTCy for GVHD prophylaxis may have a major ATG sparing potential. A recent single centre phase 2 study (n=49) suggested that PTCy alone may not be the preferred GVHD prophylaxis following a RIC transplant with PBSCs. Indeed, A matched cohort analysis compared outcomes to tacrolimus/methotrexate GVHD prophylaxis and indicated higher rates of acute GVHD grade II to IV (46% versus 19%; hazard ratio [HR], 2.8; P =0.02) and treatment-related mortality (HR, 3.3; P =0.035) and worse overall survival (HR, 1.9; P=0..04) with post-CY. Interpretation of the above non-randomized data is further complicated by heterogeneity (related and unrelated donors, BM and PBSC as stem cell source, different conditioning regimen), highlighting the need for a controlled randomized trial in a standardized setting.

The ultimate goal of this Phase IIB study is to assess the feasibility and inform the design of a subsequent phase III study. The present randomized trial is designed to compare the efficacy of the addition of PTCy to current standard of care with ATG after a Flu-Bu-based RIC regimen on GVHD prophylaxis. The protocol will use a novel endpoint for benchmarking interventions based on a composite primary endpoint of GVHD-free, relapse-free survival which measures freedom from ongoing morbidity and represents an ideal outcome measure after allo-SCT.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Graft vs Host Disease
Intervention  ICMJE
  • Drug: Cyclophosphamide
    GVHD prophylaxis: All patients will receive post-transplant 50mg/Kg/day cyclophosphamide (day +3 and +4) AND cyclosporine-A alone in case of an HLA-sibling donor, or cyclosporine-A and mycophenolate-mofetil in case of an HLA-matched unrelated donor
    Other Name: Cyclophosphamide + cyclosporine-A +/-mycophenolate-mofetil
  • Drug: Anti-Thymocyte Globulin
    GVHD prophylaxis: 2.5 mg/Kg/day ATG (Thymoglobuline®) for 2 consecutive days (day -2 and -1) All patients will receive cyclosporine-A alone in case of an HLA-sibling donor, or cyclosporine-A and mycophenolate-mofetil (MMF) in case of an HLA-matched unrelated donor.
    Other Name: Anti-Thymocyte Globulin + cyclosporine-A +/-mycophenolate-mofetil
  • Drug: Conditioning regimen
    30 mg/m2/day fludarabine for 5 days (day-6 to day-2) 130 mg/m2/day IV busulfan once daily for 2 days (day -4 and -3)
Study Arms  ICMJE
  • Experimental: Cyclophosphamide
    50mg/Kg/day cyclophosphamide (day +3 and +4)
    Interventions:
    • Drug: Cyclophosphamide
    • Drug: Conditioning regimen
  • Active Comparator: Anti-Thymocyte Globulin
    2.5 mg/Kg/day ATG (Thymoglobuline®) for 2 consecutive days (day -2 and -1)
    Interventions:
    • Drug: Anti-Thymocyte Globulin
    • Drug: Conditioning regimen
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 18, 2016)
88
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 2020
Estimated Primary Completion Date February 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria :

  • Patients aged between 18 and 65 years
  • Presence of a hematologic malignancy for which a reduced-intensity conditioning allo-SCT is indicated (eligibility criteria for RIC allo-SCT include at least one of the following parameters: (i) patient age older than 50 years; (ii) heavily pre-treated patients who received an autologous hematopoietic SCT (auto-SCT) or with more than 2 lines of chemotherapy before allo-SCT; and (iii) patients with poor performance status because of significant medical comorbidities as described by Sorror et al.
  • Karnofsky index ≥ 70%
  • Availability of a sibling or unrelated stem-cell donor (10/10-HLA matched unrelated donor)
  • Efficient contraceptive method within 1 month for women and 3 months for men after the last dose of treatment
  • Written informed consent.

Exclusion Criteria:

  • Creatinine clearance less than 30 mL/min
  • Bilirubin or amino-transferases above 3X upper normal limit
  • Cardiac ejection fraction less than 40%
  • Pulmonary impairment with <50% lung carbon monoxide diffusing capacity (DLCO)
  • Known hypersensitivity or contraindication to the use of post-transplant Cy and ATG
  • Any circumstance that precludes the use of the drugs involved in the protocol
  • Pregnancy
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Mohamad MOHTY, PU-PH 01.49.28.26.20 ext +33 mohamad.mohty@inserm.fr
Contact: Florent MALARD, CCU-AH 01.49.28.26.20 ext +33 malardf@yahoo.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02876679
Other Study ID Numbers  ICMJE P150955
2016-002129-12 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Mohamad MOHTY, PU-PH Assistance Publique - Hôpitaux de Paris
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP