Haplo vs. URD in AML
Haplo vs. URD in AML
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.
This is a randomized, intention-to-treat, open label, non-inferiority study performed in an
 international multicenter setting comparing allogeneic stem cell transplantation (SCT) with
 haplo-identical family donors (haplo SCT) to matched unrelated donor (URD) SCT in adult
 patients with de novo or treatment related acute myeloid leukemia (AML). The primary study
 objective is to compare GVHD and relapse free survival (GRFS) at 2 years post-randomization
 in patients randomized to Haplo-SCT with patients randomized to URD-SCT.

 The choice of hematopoietic stem cell donor, the humal leukocyte antigen (HLA) match, and the
 type of graft used are factors of major importance for survival and the risk of complications
 after SCT. The use of haplo-identical donors has shown very promising results and may result
 in a paradigm shift in SCT. However, no prospective randomized studies comparing unrelated
 donors, the standard choice today when no HLA-identical sibling is available, with
 haplo-identical donors have been published. The purpose of this study is to evaluate in a
 prospective and randomised fashion whether haplo-identical donor SCT could yield similar
 results to SCT with unrelated donors in patients with AML.

 HYPOTHESIS:

 The graft-vs.-host disease- and relapse-free survival two years after randomization (2-year
 GRFS) after haplo SCT is not inferior to 2-year GRFS after URD SCT with donors matched at 7/8
 or 8/8 of the major HLA loci.

 STUDY POPULATION

 Adult patients with de novo or treatment-related acute myeloid leukemia with indication for
 allogeneic stem cell transplantation (SCT). MDS-AML and significant extramedullary AML
 disease is excluded to make the study population more homogeneous.

 Main inclusion criteria: Adult patients (age ≥ 18 years) with de novo or treatment-related
 AML, eligible and fit for SCT, with at least one potential haplo-identical related donor and
 at least five potential HLA-A, -B, and -DRB1 antigen matched unrelated donors (URD)
 identified prior to inclusion.

 Main exclusion criteria: Patients with a suitable HLA-identical sibling donor, and patients
 with less than five potential URDs, and/or without a potential haplo-identical related donor.

 Sample size: The total target enrollment is 200 patients, 100 patients in each treatment arm.

 STUDY PLAN

 Randomization is performed when it has been determined that all inclusion criteria are
 fulfilled and no exclusion criteria are met. Patients will be randomized at a ratio 1:1
 between the treatment arms using the permuted block technique, stratified by center to reduce
 geographic and recruitment location related bias.

 CHOICE OF DONOR AND STEM CELL SOURCE Donors for Haplo-SCT are required to be healthy and
 18-60 years of age. Siblings, children and parents are acceptable. The choice of donor is
 based on the clinical experience and current standard procedure at each center, taking
 factors such as ABO-match, presence of relevant HLA-antibodies in the recipient,
 cytomegalovirus (CMV)-serology compatibility, female donor to male recipient, and donor age
 into consideration. The presence of significant levels of HLA-antibodies against mismatched
 HLA molecules of the donor renders that donor unsuitable for transplantation. The primary
 stem cell source for Haplo-SCT in the study is bone marrow. The target dose is > 4 ×10(8)
 total nucleated cells (TNC)/kg patient weight. Peripheral blood stem cell grafts can be used
 without breaking study protocol, but is strongly discouraged in patients where bone marrow
 harvest of the donor is possible. If PBSC is used for Haplo-SCT in this trial, the maximum
 cell dose recommended is 5 ×10(6) CD34+ cells/kg patient weight.

 The choice of URD is to be based on the standard donor selection algorithm and guidelines at
 each participating center. The chosen URD need to be allele-matched for HLA-A, -B, and -DRB1.
 For HLA-C, one allele or antigen mismatch is allowed. If the HLA-match between the recipient
 and several URDs are acceptable, other donor SCT-factors (e.g. CMV-status, ABO-compatibility,
 sex-match, previous pregnancies, age, weight, etc.) should be taken into consideration before
 the final donor choice. The choice of stem cell source (BM or PBSC) and CD34+ cell dose and
 total nucleated cell dose should be according to current institutional practice.

 For patients randomized to either treatment arm where no suitable donor can be identified,
 cross over to the other arm is permitted.

 TREATMENT PLAN

 CONDITIONING:

 Patients randomized to haplo SCT will be treated according to the Genoa protocol. This
 protocol is based on the administration of 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). For elderly patients (> 60
 years), or patients in poor clinical condition, the dose of busulfan may be reduced (e.g. by
 reducing the number of treatment days, usually to 2 days for patients > 60 years old). GVHD
 prophylaxis for Haplo-SCT is cyclophosphamide 50 mg/kg day +3 and +5, cyclosporin A (CyA) and
 mycophenolate mofetil (MMF).

 Patients randomized to URD SCT are treated according to the conditioning protocols used in
 standard practice, with a recommendation to use the conditioning regimens "Flu+Bu"
 (fludarabine + busulfan, with a total dose of Bu 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). If possible, all participating centers are recommended to use one
 myeloablative conditioning (MAC) protocol and one reduced intensity (RIC) protocol for
 included URD-SCT study patients throughout the study. In the majority of the participating
 centers, protocols including anti-thymocyte globulin (ATG) is administered. The choice of
 GVHD prophylaxis for the URD-SCT arm is to be performed according to the same principle as
 the conditioning regimen, i. e. the standard practice at the center should be applied.

 IMMUNOSUPPRESSION:

 The dose of CyA should be targeted and adjusted to a set serum concentration as per center
 preference. As a general guide, patients that have undergone Haplo-SCT could be kept at a
 slightly lower concentration compared to patients that have undergone URD-SCT. The guiding
 dosage principle is that CyA is given i.v. or p.o. at full dose from day 0 in the Haplo-SCT
 arm (from day -1 in the URD-SCT patients receiving CyA) to day +90 approximately, then to be
 tapered in the absence of GvHD and discontinued at 5-6 months after SCT or earlier if
 clinically indicated. Tacrolimus may replace CyA if the patient does not tolerate CyA.

 In haplo SCT patients, MMF is given at 15 mg/kg x 2 orally, starting at day +1 post SCT. It
 is recommended to use MMF orally, but i.v. MMF is accepted. Dose adjustment is necessary in
 patients suffering from severely impaired kidney or liver function. MMF is discontinued day
 +28. In case MMF is used in URD-SCT patients, this is to be done according to the standard
 protocols of the transplant center concerned.

 Other relevant GVHD prophylaxis strategies for URD-SCT are also permitted.

 SUPPORTIVE CARE

 Supportive care is to be performed according to standard procedure at each participating
 center.

 FOLLOW UP

 Patients will be followed for GRFS, survival, relapse, and other listed end-points at
 designated time points. The primary endpoint will be reached when the last included patient
 has a follow-up time of 2 years. The study will be terminated when the last included patient
 has a follow-up time of five years. Data collection is continued even if the assigned therapy
 was not carried out, since the main study analyses are intention-to-treat analyses.
 Per-protocol analyses will be performed as well.

 STUDY-SPECIFIC SAMPLES

 Study samples from peripheral blood:

 Study samples from peripheral blood are requested at the visit for randomization, at the day
 of SCT-graft infusion (day 0), and at follow-up visits after 1, 3, 6, 12 and 24 months
 post-SCT. At all of these time-points,

 Study samples from bone marrow:

 Study samples from bone marrow aspiration material are requested at the follow-up visits
 after 2-3, 6, 12 and 24 months post-SCT (see Appendix IV for reference). At all of these
 time-points,

 STUDY MANAGEMENT

 Source data and data management Data will be collected continuously and entered into the
 study specific electronic case report form (eCRF). Study-related documents will be retained
 for at least 25 years.

 Quality control and monitoring The study will be monitored regularly according to good
 clinical practice (GCP) and local regulations to ensure accurate, complete and reliable data.
 All information reported in the eCRF will also be documented in the patient's file unless
 otherwise specified.

 Patient information and consent Before inclusion patients will receive verbal and written
 information including a description of the trial, its purpose, the risks and the procedures
 involved. Written informed consent must be obtained from all patients before enrollment in
 the study.

 Adverse Event (AE) Reporting Reported in the eCRF according to CTCAE version 4.03.

 Serious Adverse Event (SAE) reporting For the purpose of this study, SAEs that are regarded
 as expected events considering the given treatment (i.e. allogeneic hematopoietic stem cell
 transplantation) and underlying disease, need not be reported as SAEs. However, all deaths
 and unexpected significant SAEs are to be reported.

 Study Safety Board A Study Safety Board (SSB) will perform safety analyses during the study.
 This is a study independent data-monitoring committee that is established by the Sponsor to
 assess at intervals the progress of the clinical trial, the safety data, and the critical
 endpoints of the trial. The SSB will consist of three members, with at least one independent
 statistician and two internationally renowned clinical hematologists.

 The SSB will receive at least the following reports from the trial statistician for review:

 -  Interim analysis reports when 50% of the patients have been included, and when 100% of
 the patients have been included in the trial.

 -  Annual safety data listing the incidence of (serious) adverse events.

 -  Annual progress data listing the number of enrolled patients and the status of data
 collection.

 Study termination and stopping rules

 Regular study termination The study will be terminated when the last included surviving
 patient has a follow-up of five years in the trial.

 Stopping rules Termination of the study will be considered if, at the first interim analysis,
 the rate of non-relapse mortality (NRM) ≥ 40% at 200 days after SCT, and/or the rate of acute
 GVHD grades III-IV ≥ 20% in evaluable patients (with sufficient follow-up time or evaluation)
 in the Haplo-SCT arm.
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.