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Haplo vs. URD in AML

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ClinicalTrials.gov Identifier: NCT04067180
Recruitment Status : Recruiting
First Posted : August 26, 2019
Last Update Posted : February 5, 2020
Sponsor:
Collaborators:
Skane University Hospital
Uppsala University Hospital
University Hospital, Linkoeping
University Hospital, Umeå
Karolinska Institutet
Sahlgrenska University Hospital, Sweden
Oslo University Hospital
Helsinki University Central Hospital
St. Petersburg State Pavlov Medical University
Princess Margaret Hospital, Canada
Medical University of Vienna
Information provided by (Responsible Party):
Jonas Mattsson, Karolinska Institutet

Brief Summary:

This study compares haplo-identical family donor stem cell transplantation (haplo SCT) to matched unrelated donor transplantation (URD SCT) in adult patients with acute myeloid leukemia (AML) with the hypothesis that haplo SCT is as good as URD SCT.

Background:

A haplo-identical family donor is a relative sharing 50% of the human leukocyte antigens (HLA) of the patient. SCT with this type of donor is increasing, and a number of retrospective studies have demonstrated its feasibility, but prospective randomized studies are still lacking. Such studies are necessary to establish the benefits of haplo SCT. For the ≈70% of the patients that lack the 1st choice donor, an HLA-matched sibling, the 2nd choice is an URD at most centers. However, if haplo-identical donors are as good as URDs, this could change. Haplo-identical donors have several advantages. Almost all patients have at least one available haplo-identical donor, while URDs can be difficult to find. It also eliminates the need for time-consuming donor searches, and is considerably less costly.

The Study:

Patients can be included in the study if they have AML and require SCT, ≥18 years, DO NOT have an HLA-matched sibling donor, and DO have potential haplo-identical family donors AND URDs.

After enrollment in the study, the patients are assigned randomly to either haplo SCT or URD SCT. The treatment surrounding the transplantation differs according to the donor type. Patients receiving haplo-identical transplantation are treated with a specified chemotherapy protocol before transplantation and a chemotherapy combined with immunosuppressive drugs after the transplantation to prevent graft-vs. host disease (GVHD). The patients receiving URD SCT will be treated according to the standard protocol at their center. Thus, haplo SCT will be compared to what is currently used in patients without an HLA-identical sibling today.

The primary endpoint of this study is graft-vs.-host disease- and relapse free survival two years after study inclusion. This measurement takes into account the side effect that causes the most long-term suffering, graft-vs-host disease, as well as leukemia relapse and thus indicates to what extent the treated patients remain relapse-free and without significant side effects. Secondary end points include relapse-free survival, frequencies of graft-versus-host disease and of infections, and the patients will be followed in the study for five years.


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Other: allogeneic stem cell transplantation with a haplo-identical family donor graft Other: allogeneic stem cell transplantation with a matched unrelated donor graft Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized Clinical Study of Haplo-Identical Donors Versus Unrelated Donors in Hematopoietic Stem Cell Transplant Patients With Acute Myeloid Leukemia
Actual Study Start Date : November 12, 2019
Estimated Primary Completion Date : August 2027
Estimated Study Completion Date : August 2028


Arm Intervention/treatment
Experimental: Haplo SCT
Allogeneic stem cell transplantation with a haplo-identical family donor graft.
Other: allogeneic stem cell transplantation with a haplo-identical family donor graft

The graft should preferably be bone marrow, but peripheral stem cells are also acceptable.

Pre-conditioning: thiotepa 5 mg/kg/day for two days (day -6, -5), busulfan at 3,2 mg/kg/day (i.v.) and fludarabine at 50 mg/m2 (i.v.) for three consecutive days (day -4, -3, -2). Intravenous busulfan can be replaced by orally administered busulfan at a dose of 4 mg/kg/day on 3 consecutive days (day -4, -3, -2).

GVHD prophylaxis: cyclophosphamide 50 mg/kg day +3 and +5, cyclosporin A and mycophenolate mofetil.


Active Comparator: URD SCT
Allogeneic stem cell transplantation with a matched unrelated donor graft.
Other: allogeneic stem cell transplantation with a matched unrelated donor graft

Patients are treated according to the standard conditioning protocols developed for URD SCT at each participating center, with a recommendation to use "Flu+Bu" (fludarabine + busulfan, with a total Bu dose of 8-16 mg/kg body weight orally, or 6,4-12,8 mg/kg i.v.) or "Bu+Cy" (busulfan + cyclophosphamide, with a dose of Cy not exceeding 50 mg/kg x 2).

The standard GVHD prophylaxis at the center should be applied.





Primary Outcome Measures :
  1. 2-year graft-vs.-host disease- and relapse-free survival [ Time Frame: 2 years ]
    Defined in this study as the time between inclusion and either grades III-IV acute GVHD, severe chronic GVHD or disease relapse. All events occuring from SCT to last follow-up are considered when calculating GRFS. Incomplete data resulting from patients who are lost to follow-up or who withdraw their informed consent will be censored at the date they were last known to be alive. Patients who are alive at study termination will be censored at the latest date of contact. Analysed according to original treatment arm assignment (intention-to-treat)


Secondary Outcome Measures :
  1. 2-year graft-vs.-host disease- and relapse-free survival [ Time Frame: 2 years ]
    The time between inclusion and either grades III-IV acute GVHD, severe chronic GVHD or disease relapse. Analysed according to received treatment (per protocol)

  2. 5-year graft-vs.-host disease- and relapse-free survival [ Time Frame: 5 years ]
    The time between inclusion and either grades III-IV acute GVHD, severe chronic GVHD or disease relapse. Intention to treat analysis.

  3. 5-year graft-vs.-host disease- and relapse-free survival [ Time Frame: 5 years ]
    The time between inclusion and either grades III-IV acute GVHD, severe chronic GVHD or disease relapse. Per protocol analysis.

  4. Overall survival [ Time Frame: 2 years and 5 years ]
    Defined as the time interval between the date of study inclusion and the date of death from any cause. Incomplete data resulting from patients who are lost to follow-up or who withdraw their informed consent will be censored at the date they were last known to be alive. Patients who are alive at study termination will be censored at the latest date of contact. Analysed according to original treatment arm assignment (intention-to-treat)

  5. Disease-free survival [ Time Frame: 2 years and 5 years ]
    The time between date of inclusion and date of relapse or death from any cause. Incomplete data resulting from patients who are lost to follow-up or who withdraw their informed consent will be censored at the date they were last known to be alive. Patients who are alive at study termination will be censored at the latest date of contact. Analysed according to original treatment arm assignment (intention-to-treat)

  6. Overall survival [ Time Frame: 2 years and 5 years ]
    Defined as the time interval between the date of study inclusion and the date of death from any cause. Analysed according to received treatment (per protocol)

  7. Disease-free survival [ Time Frame: 2 years and 5 years ]
    Defined as the time between date of inclusion and date of relapse or death from any cause.. Analysed according to received treatment (per protocol)

  8. Acute graft.vs.-host disease [ Time Frame: 2 years ]
    Cumulative incidence of acute graft-vs.-host disease grades I-IV

  9. Chronic graft.vs.-host disease [ Time Frame: 2 years and 5 years ]
    Cumulative incidence of chronic graft-vs.-host disease

  10. Infection [ Time Frame: 2 years ]
    Cumulative incidence of infectious complications after transplantation, including bacterial blood-stream infections, fungal infections, viral infections such as cytomegalovirus and Epstein-Barr virus and other infections.

  11. Relapse [ Time Frame: 2 years and 5 years ]
    Relapse of the patients

  12. Engraftment of neutrophil granulocytes [ Time Frame: 90 days ]
    Cumulative incidence of neutrophil granulocyte engraftment (defined as reaching ≥0.5 x 10(9)/L in peripheral blood) after transplantation.

  13. Engraftment of thrombocytes [ Time Frame: 1 year ]
    Cumulative incidence of thrombocyte engraftment (defined as reaching ≥30 and ≥50 x 10(9)/L in peripheral blood) after transplantation.

  14. Other non-specified transplant complications [ Time Frame: 2 years ]
    A wide variety of transplant complications are known to occur, such as organ damage and organ failure due to the conditioning and other transplant-related treatments. The occurrence of such will be analysed.

  15. Secondary malignancies [ Time Frame: 5 years ]
    The development of malignancies after transplantation, excluding relapse of the original AML the patient received transplantation for.



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.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 1. Adult patients (age ≥ 18 years) with de novo or treatment-related AML, eligible and fit for SCT treatment according to national/international guidelines.
  • 2. One or more potential haplo-identical related donor(s) AND five or more potential 6/6 HLA-A, -B, and -DRB1 antigen matched unrelated donors identified before randomization.
  • 3. Karnofsky Performance Status ≥ 70% at randomization.
  • 4. Signed informed consent.
  • 5. Patient willing and able to comply with protocol requirements

Exclusion Criteria:

  • 1. Patients with a suitable HLA-identical sibling donor.
  • 2. Patients with < 5 potential HLA-A, -B, and -DRB1 antigen matched URDs available.
  • 3. Patients with no potential haplo-identical related donor available.
  • 4. Patients scheduled for/receiving cord blood stem cell transplantation.
  • 5. Prior allogeneic SCT using any hematopoietic stem cell source.
  • 6. Patients seropositive for HIV.
  • 7. Pregnancy (positive β-HCG test) within 4 weeks of study entry.
  • 8. Cardiac ejection fraction < 45%.
  • 9. Karnofsky Performance Status < 70% at time of randomization.
  • 10. The presence of any psychological, family-related, social, and/or geographical condition potentially jeopardizing compliance with the study protocol and follow-up schedule.

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): NCT04067180


Contacts
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Contact: Jonas Mattsson, MD PhD, Prof +46702456221 jonas.mattsson@ki.se
Contact: Sofia Berglund, MD PhD +46704244237 sofia.berglund@ki.se

Locations
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Austria
Medical University of Vienna Not yet recruiting
Vienna, Austria, 1090
Contact: Phillip Wohlfarth, MD       philipp.wohlfarth@meduniwien.ac.at   
Contact: Hanna Knaus, MD PhD       hanna.knaus@meduniwien.ac.at   
Canada, Ontario
Princess Margaret Cancer Centre Not yet recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: Rajat Kumar, MD, FRCP, Prof       Rajat.Kumar@uhn.ca   
Contact: Arjun D Law, MD DM, Ass. Prof       Arjun.Law@uhn.ca   
Finland
Helsinki University Central Hospital Not yet recruiting
Helsinki, Finland, FI-00290
Contact: Riitta Niittyvuopio, MD       riitta.niittyvuopio@hus.fi   
Norway
Oslo University Hospital Recruiting
Oslo, Norway, NO-0424
Contact: Yngvar Fløisand, MD PhD       Yngvar.Floisand@oslo-universitetssykehus.no   
Contact: Tobias Gedde-Dahl, MD PhD       tgeddeda@ous-hf.no   
Russian Federation
Pavlov First Saint-Petersburg State Medical University Recruiting
Saint Petersburg, Russian Federation, 197022
Contact: Boris V Afanasyev, MD PhD       bmt-director@1spbgmu.ru   
Contact: Ivan S Moiseev, MD PhD       moisiv@mail.ru   
Sub-Investigator: Sergey Bondarenko, MD PhD         
Sub-Investigator: Anna Smirnova, MD PhD         
Sweden
Sahlgrenska University Hospital Not yet recruiting
Gothenburg, Sweden, SE-413 45
Contact: Jan-Erik Johansson, MD PhD       Jan-Erik.J.Johansson@vgregion.se   
Contact: Mats Brune, MD PhD       Brune@gu.se   
Linköping University Hospital Not yet recruiting
Linköping, Sweden, SE-581 85
Contact: Jörg Cammenga, MD PhD       Jorg.Cammenga@regionostergotland.se   
Skåne University Hospital Not yet recruiting
Lund, Sweden, SE-221 85
Contact: Stig Lenhoff, MD PhD       Stig.Lenhoff@skane.se   
Karolinska University Hospital Not yet recruiting
Stockholm, Sweden, SE-141 86
Contact: Stephan Mielke, MD PhD       Stephan.Mielke@sll.se   
Contact: Per Ljungman, MD PhD       Per.Ljungman@sll.se   
Umeå University Hospital Not yet recruiting
Umeå, Sweden, SE-901 85
Contact: Cecilia Isaksson, MD       Cecilia.Isaksson@vll.se   
Contact: Maria Liljeholm, MD PhD       Maria.Liljeholm@vll.se   
Uppsala University Hospital Not yet recruiting
Uppsala, Sweden, SE-751 85
Contact: Kristina Carlson, MD PhD       Kristina.Carlson@akademiska.se   
Contact: Ulla Ollson-Strömberg, MD PhD       Ulla.Olsson-Stromberg@medsci.uu.se   
Sponsors and Collaborators
Jonas Mattsson
Skane University Hospital
Uppsala University Hospital
University Hospital, Linkoeping
University Hospital, Umeå
Karolinska Institutet
Sahlgrenska University Hospital, Sweden
Oslo University Hospital
Helsinki University Central Hospital
St. Petersburg State Pavlov Medical University
Princess Margaret Hospital, Canada
Medical University of Vienna
Investigators
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Study Chair: Johan Karlsson Torlen, MD PhD Karolinska Institutet
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Responsible Party: Jonas Mattsson, Professor, Karolinska Institutet
ClinicalTrials.gov Identifier: NCT04067180    
Other Study ID Numbers: DNR: 2017/8
First Posted: August 26, 2019    Key Record Dates
Last Update Posted: February 5, 2020
Last Verified: February 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Jonas Mattsson, Karolinska Institutet:
allogeneic stem cell transplantation
Haplo-identical donors
Matched unrelated donors
Alternative stem cell donors
Post-transplantation cyclophosphamide
Haplo-identical stem cell transplantation
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms