We're building a better ClinicalTrials.gov. Check it out and tell us what you think!
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

HLA 10/10 Matched Unrelated Donor vs Haploidentical Allogenic Hematopoietic Stem Cell Transplantation (MacHaploMud)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03655145
Recruitment Status : Not yet recruiting
First Posted : August 31, 2018
Last Update Posted : August 31, 2018
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Study Description
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Brief Summary:
The MAC-HAPLO-MUD trial is a randomized prospective phase III trial comparing HLA 10/10 matched unrelated donor and haploidentical allogeneic hematopoietic stem cell transplantation after myeloablative conditioning regimen in patients, age 15 years or older, with Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL) or Myeloproliferative Syndrome (SMP) or Myelodysplastic Syndromes (SMD) and requiring allogeneic hematopoietic stem cell transplantation. Primary endpoint is the 1-year progression free survival without acute grade II-IV GvHD and without moderate and severe chronic GvHD.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Acute Lymphoblastic Leukemia Myeloproliferative Syndromes Myelodysplastic Syndromes Other: Haplo donor stem cell transplantation Other: HLA 10/10 MUD stem cell transplantation Phase 3

Detailed Description:

An unrelated adult donor who is HLA-matched to the recipient at the allele-level (at HLA-A, -B, -C, -DQB1 and -DRB1) is considered the best choice in the absence of an HLA-matched sibling for patients needing hematopoietic stem cell transplantation (SCT).

However, using matched unrelated donors (MUD) is limited by (1) a prolonged time to identify and schedule donation for some MUD allowing some patients to relapse before transplantation can be performed, and (2) limited availability of fully HLA-MUD for the non-Caucasian population.

Alternative donors are used for transplantation in patients without a fully-MUD including single HLA mismatched unrelated donor, unrelated umbilical cord blood and grafts from haploidentical related donors but are associated with higher non-relapse mortality and delayed immune reconstitution.

A more recent strategy for haploidentical (haplo) related donor SCT (haplo-SCT) has improved dramatically outcomes using T-cell replete grafts with administration of post-transplantation cyclophosphamide (PTCy).

From retrospective studies, haplo-SCT with PTCy are associated with similar overall and progression-free survivals as with MUD stem cell transplantation (MUD-SCT), but with lower rates of toxicity and graft versus host disease (GvHD), and thus potentially better results than MUD-SCT after reduced intensity conditioning (RIC) regimen. Haplo-SCT with PTCy is thus highly discussed nowadays motivating prospective trials to confirm the benefit of this procedure.

In the setting of a myeloablative conditioning (MAC) regimen in adults with high risk hematological malignancies, few retrospective non-controlled registry studies recently suggest that outcomes after haplo-SCT using PTCy approach might also be superior in terms of GVHD free survival to that after MUD stem cell transplantation (MUD-SCT).

The investigators propose to address this question, in a randomized prospective phase III clinical trial comparing HLA 10/10 MUD and haplo-SCT after MAC regimen. The stem cell source will be bone marrow for haploidentical SCT and peripheral blood stem cell (PBSC) for HLA-matched unrelated transplantation.

The primary endpoint is the 1-year progression free survival without acute grade II-IV GvHD and without moderate and severe chronic GvHD.

Study Design
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 344 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized prospective Phase III clinical trial comparing HLA 10/10 matched unrelated donor (standard arm) and haploidentical allogeneic hematopoietic stem cell transplantation (experimental arm) after myeloablative conditioning regimen
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized Prospective Phase III Clinical Trial Comparing HLA 10/10 Matched Unrelated Donor and Haploidentical Allogenic Hematopoietic Stem Cell Transplantation After Myeloablative Conditioning Regimen
Estimated Study Start Date : August 2018
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : June 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Organ Donation

Arms and Interventions
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm Intervention/treatment
Experimental: Haploidentical donor stem cell transplantation
The stem cell source will be bone marrow for haploidentical transplantation.The bone marrow collection is carried out according to the practice of each centre with a minimal target dose of 3x108 TNC/kg.
 Other: Haplo donor stem cell transplantation
The algorithm for selection of haploidentical donor has been defined by the french society for stem cell transplantation The stem cell source will be bone marrow for haploidentical transplantation.The bone marrow collection is carried out according to the practice of each centre with a minimal target dose of 3x108 TNC/kg.
Active Comparator: HLA 10/10 MUD stem cell transplantation
The stem cell source will be peripheral blood stem cell for HLA-matched unrelated transplantation.Peripheral blood stem cell (PBSC) for HLA-matched unrelated SCT will be mobilized by G-CSF (Neupogen®) administered to the donor from Day-4 to Day-1 subcutaneously (10µg/kg/day) with the minimal target dose of 4.106 CD34+ cells/kg.
 Other: HLA 10/10 MUD stem cell transplantation
HLA 10/10 matched unrelated donor myeloablative transplantation


Outcome Measures
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :
  1. Progression free survival, without acute grade II-IV GvHD and without moderate and severe chronic GvHD. [ Time Frame: 12 months ]

    One year progression free survival, without acute grade II-IV GvHD and without moderate and severe chronic GvHD.

    -Relapse evaluation:

    For myeloid malignancies, the relapse will be defined by the reappearance of leukemic cells after SCT.

    For ALL, the relapse will be defined by: the reappearance of leukemic cells after SCT and/or an increase of at least 50 % of the smallest measure of any lymphnode considered abnormal in the pre-transplantation period for patients in partial response and in non-responders and/or the appearance of any new lesion in comparison with the pre-transplantation period evaluation.

    - GvHD evaluation:

    Grading of acute GVHD will be performed according to the classification of Glusckberg.

    Grading of chronic GVHD will be performed according to the NIH classification.



Secondary Outcome Measures :
  1. Time interval between indication of stem cell transplantation (SCT) and transplant [ Time Frame: 24 months ]
  2. Engraftment [ Time Frame: at 24 months ]
    Engraftment: at least 3 consecutive days with neutrophils > 0.5 G/L, with platelets > 20 G/L

  3. Numbers of neutrophils [ Time Frame: at 1 month ]
    Absolute numbers of neutrophils

  4. Numbers of platelets [ Time Frame: at 1 month ]
    Absolute numbers of platelets

  5. Numbers of neutrophils [ Time Frame: at 2 months ]
    Absolute numbers of neutrophils

  6. Numbers of platelets [ Time Frame: at 2 months ]
    Absolute numbers of platelets

  7. Numbers of neutrophils [ Time Frame: at 3 months ]
    Absolute numbers of neutrophils

  8. Numbers of platelets [ Time Frame: at 3 months ]
    Absolute numbers of platelets

  9. Numbers of neutrophils [ Time Frame: at 6 months ]
    Absolute numbers of neutrophils

  10. Numbers of platelets [ Time Frame: at 6 months ]
    Absolute numbers of platelets

  11. Numbers of neutrophils [ Time Frame: at 12 months ]
    Absolute numbers of neutrophils

  12. Numbers of platelets [ Time Frame: at 12 months ]
    Absolute numbers of platelets

  13. Numbers of neutrophils [ Time Frame: at 24 months ]
    Absolute numbers of neutrophils

  14. Numbers of platelets [ Time Frame: at 24 months ]
    Absolute numbers of platelets

  15. Use of growth factors [ Time Frame: at 12 months ]
    Use of growth factors for poor hematopoietic reconstitution

  16. Immune reconstitution [ Time Frame: at 1 month post transplantation ]
    Immune reconstitution by analyzing T, B, Natural Killer (NK), regulatory T cell levels in the peripheral blood

  17. Immune reconstitution [ Time Frame: at 3 months post transplantation ]
    Immune reconstitution by analyzing T, B, NK, regulatory T cell levels in the peripheral blood

  18. Immune reconstitution [ Time Frame: at 6 months post transplantation ]
    Immune reconstitution by analyzing T, B, NK, regulatory T cell levels in the peripheral blood

  19. Immune reconstitution [ Time Frame: at 12 months post transplantation ]
    Immune reconstitution by analyzing T, B, NK, regulatory T cell levels in the peripheral blood

  20. Immune reconstitution [ Time Frame: at 24 months post transplantation ]
    Immune reconstitution by analyzing T, B, NK, regulatory T cell levels in the peripheral blood

  21. Iron overload estimation [ Time Frame: at 1 month ]
  22. Iron overload estimation [ Time Frame: at 3 months ]
  23. Iron overload estimation [ Time Frame: at 6 months ]
  24. Iron overload estimation [ Time Frame: at 12 months ]
  25. Iron overload estimation [ Time Frame: at 24 months ]
  26. Chimerism [ Time Frame: at 1 month ]
  27. Chimerism [ Time Frame: at 3 months ]
  28. Chimerism [ Time Frame: at 6 months ]
  29. Chimerism [ Time Frame: at 12 months ]
  30. Acute GvHD [ Time Frame: at 24 months ]
    Incidence of acute GvHD

  31. First line treatment [ Time Frame: 24 months ]
  32. Response to steroids [ Time Frame: 24 months ]
  33. Treatment courses for refractory aGVHD [ Time Frame: 24 months ]
  34. Relapse [ Time Frame: 24 months ]
    Incidence of relapse

  35. Progression free survival [ Time Frame: 24 months ]
  36. Severe infections (CTAE grade 3-4) [ Time Frame: 12 months ]
  37. Cytomegalovirus (CMV) [ Time Frame: 12 months ]
    Incidence of CMV

  38. Epstein-Barr virus (EBV) [ Time Frame: 12 months ]
    Incidence of EBV reactivation

  39. Veno-occlusive disease (VOD) [ Time Frame: 3 months ]
    Incidence of veno-occlusive disease

  40. Severity of veno-occlusive disease (VOD) [ Time Frame: 3 months ]

    Severity of veno-occlusive disease. VOD severity will be assessed using new EBMT criteria (Mohty et al., 2016). EBMT criteria for grading VOD severity in adult patients are based on the level of bilirubin and its rate of change, liver function (transaminase), weight increase, renal function and the kinetic of their onset (Mohty et al., 2016). This grading system is divided into five categories as following: mild, moderate; severe, very severe; and death.

    Mohty M., Malard F., Abecassis M., Aerts E., Alaskar AS. et al. (2016). Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplantation 51,906-912.


  41. Cardiac toxicities [ Time Frame: 12 months ]
    Incidence of cardiac toxicities

  42. Non-relapse mortality [ Time Frame: 12 months ]
  43. Overall survival [ Time Frame: 24 months ]
    Time between death and inclusion

  44. Quality of life post transplantation: EORTC QLQ-C30- v3 [ Time Frame: 1 week post-transplantation ]

    Quality of life evaluated using questionnaire "European Organization for Research and Treatment of Cancer Quality of Life Questionnaire" (EORTC QLQ-C30- v3). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems.

    EORTC QLQ-C30 Scoring Manual. Fayers PM et al. on behalf of the EORTC Quality of Life Group. EORTC, 2001. ISBN: 2-9300.


  45. Quality of life at 3 months: EORTC QLQ-C30- v3 [ Time Frame: 3 months ]

    Quality of life evaluated using questionnaire "European Organization for Research and Treatment of Cancer Quality of Life Questionnaire" (EORTC QLQ-C30- v3). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems.

    EORTC QLQ-C30 Scoring Manual. Fayers PM et al. on behalf of the EORTC Quality of Life Group. EORTC, 2001. ISBN: 2-9300.


  46. Quality of life at 6 months: EORTC QLQ-C30- v3 [ Time Frame: 6 months ]

    Quality of life evaluated using questionnaire "European Organization for Research and Treatment of Cancer Quality of Life Questionnaire" (EORTC QLQ-C30- v3). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems.

    EORTC QLQ-C30 Scoring Manual. Fayers PM et al. on behalf of the EORTC Quality of Life Group. EORTC, 2001. ISBN: 2-9300.


  47. Quality of life at 12 months: EORTC QLQ-C30- v3 [ Time Frame: 12 months ]

    Quality of life evaluated using questionnaire "European Organization for Research and Treatment of Cancer Quality of Life Questionnaire" (EORTC QLQ-C30- v3). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems.

    EORTC QLQ-C30 Scoring Manual. Fayers PM et al. on behalf of the EORTC Quality of Life Group. EORTC, 2001. ISBN: 2-9300.


  48. Quality of life at 24 months: EORTC QLQ-C30- v3 [ Time Frame: 24 months ]

    Quality of life evaluated using questionnaire "European Organization for Research and Treatment of Cancer Quality of Life Questionnaire" (EORTC QLQ-C30- v3). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems.

    EORTC QLQ-C30 Scoring Manual. Fayers PM et al. on behalf of the EORTC Quality of Life Group. EORTC, 2001. ISBN: 2-9300.


  49. Number of new days of hospitalization after the hospitalization for transplantation [ Time Frame: at 24 months ]

Eligibility Criteria
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   15 Years to 55 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • With AML/ALL/SMD/SMP requiring allogeneic stem cell transplantation
  • In complete response (CR) for AML/ALL or in CR, or partial response (PR) or non pre-treated for SMD/SMP *
  • Without a HLA matched related donor available
  • With a good probability to have a HLA-10/10 matched donor available (the patient needs to have at least 5 MUD identified within the book "BMDW (Bone Marrow Donors Worldwide)"
  • With identification of a haploidentical donor (brother, sister, parents, adult children or cousin)
  • Absence of donor specific antibody (DSA) detected in the patient with a MFI ≥ 2000 (antibodies directed towards the distinct haplotype between donor and recipient)

With usual criteria for hematopoietic stem cell transplant (HSCT):

  • Eastern Cooperative Oncology Group (ECOG) ≤ 2
  • No severe and uncontrolled infection
  • Cardiac function compatible with high dose of cyclophosphamide

  • Adequate organ function: aspartate transaminase (ASAT) and alanine aminotransferase (ALAT) ≤ 2N, total bilirubin ≤ 1.5N, creatinine clearance ≥30ml/min (except if those abnormalities are linked to the hematological disease)

    • With health insurance coverage
    • Understand informed consent or optimal treatment and follow-up
    • Contraception methods must be prescribed during all the duration of the research and using effective contraceptive methods during treatment and within 12 months for women and 6 months for men after the last dose of cyclophosphamide
    • Having signed a written informed consent (2 parents for patients aged less than 18)

Exclusion Criteria:

  • Presence of donor specific antibody (DSA) with a MFI ≥ 2000 detected in the patient
  • History of Cancer in the last 5 years (except basal cell carcinoma of the skin or "in situ" carcinoma of the cervix)
  • Uncontrolled infection
  • Seropositivity for HIV or HTLV-1 or active hepatitis B or C defined by a positive polymerase chain reaction (PCR) hepatitis B virus (HBV) or hepatitis C virus (HCV) and hepatic cytolysis due to HBV
  • Yellow fever vaccine within 2 months before transplantation
  • Uncontrolled coronary insufficiency, recent myocardial infarction <6 month, current manifestations of heart failure, uncontrolled cardiac rhythm disorders, ventricular ejection fraction <50%
  • Heart failure according to New York Heart Association (NYHA) (II or more)
  • Urinary tract obstruction
  • Contraindications to treatments used during the research
  • Preexisting acute hemorrhagic cystitis
  • Renal failure with creatinine clearance <30ml / min
  • Pregnancy ( β- human chorionic gonadotropin (β-HCG positive)) or breast-feeding
  • Any debilitating medical or psychiatric illness which would preclude the realization of the SCT or the understanding of the protocol
  • Under protection by law (tutorship or curatorship)
  • Unwilling or unable to comply with the protocol
Contacts and Locations
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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): NCT03655145


Contacts
Layout table for location contacts
Contact: Régis Peffault de Latour +33142385073 regis.peffaultdelatour@aphp.fr
Contact: Sylvie Chevret +33142499742 sylvie.chevret@paris7.jussieu.fr

Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
More Information
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Layout table for additonal information
Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03655145    
Other Study ID Numbers: AOM 17030
First Posted: August 31, 2018    Key Record Dates
Last Update Posted: August 31, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
 Bone Marrow Diseases
Hematologic Diseases
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases