Randomized Clinical Study Assessing Haplo vs. URD in AML

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.