A multi-centre phase II trial of GvHD prophylaxis following unrelated donor stem cell transplantation comparing Thymoglobulin vs. Calcineurin inhibitor or Sirolimus-based post-transplant cyclophosphamide.

This is a prospective, phase II, adaptive, multicentre, randomised clinical trial in patients undergoing reduced intensity conditioned (RIC) unrelated donor allogeneic stem cell transplantation (allo-SCT). The trial will compare the novel graft-versus-host disease (GvHD) prophylaxis regimens of post-transplant cyclophosphamide (PTCy) + Calcineurin inhibitor (CNI) (PTCy-CNI) or PTCy + Sirolimus to a current standard-of-care involving the use of T-cell depletion with Thymoglobulin. Patients will be minimised at randomisation by their randomising centre, disease risk score (low/intermediate or high/very high) and human leukocyte antigen (HLA) match (10/10 or 9/10). Patients eligible for entry into the trial will be randomised on a 1:1:1 ratio to receive either one of the experimental treatment arms or the control arm.

The primary objective is to compare GvHD-free, relapse-free Survival (GRFS) in patients treated with the GvHD prophylaxis regimens PTCy-CNI, PTCy-Sirolimus or T-cell depletion with Thymoglobulin.

The secondary objectives are to evaluate the cumulative incidence of acute GvHD (aGvHD), the cumulative incidence of moderate and severe chronic GvHD (cGvHD), the cumulative incidence of non-relapse mortality (NRM), overall survival (OS), progression-free survival (PFS), immune suppression-free survival, the cumulative incidence of engraftment, the incidence of full donor chimerism, the cumulative incidence of infection requiring inpatient admission, the number of inpatient days, the timing and dose of donor lymphocyte infusion (DLI), the cumulative incidence of Epstein-Barr virus (EBV) related-post transplant lymphoproliferative disease (PTLD), the number of doses rituximab administered for EBV reactivation, quality of life (QoL), the cumulative incidence of haemorrhagic cystitis, the cumulative incidence of cytomegalovirus (CMV) viraemia and CMV end-organ disease and safety and tolerability.

The scientific research will address the questions about how plasma biomarkers for GvHD predict GvHD and non-relapse mortality following T-cell depleted methods of transplantation and how the different methods of T-cell depletion impact on immune function and re-constitution.

Outcome Measures

Primary Outcome Measure:

• GvHD-free, relapse-free survival at 1 year

Secondary Outcome Measures:

• Cumulative incidence of acute grade II-IV and III-IV GvHD at 1 year
• Cumulative incidence of moderate and severe chronic GvHD at 1 year
• Cumulative incidence of NRM at 1 year
• Overall survival at 1 year
• Progression-free survival at 1 year
• Immune suppression-free survival at 1 year
• Cumulative incidence of engraftment at 1 year
• The incidence of full donor chimerism at 100 days
• The cumulative incidence of infection requiring inpatient admission at 1 year
• The number of inpatient days during first 12 months
• The timing and dose of DLI for mixed chimerism, persistent disease or relapse
• Cumulative incidence of EBV-related PTLD
• The number of doses of rituximab administered for EBV reactivation during first 12 months
• QoL measured by FACT-BMT questionnaire at baseline, 6 months and 12 months
• Cumulative incidence of patients with haemorrhagic cystitis at 1 year
• Cumulative incidence of CMV viremia and CMV end-organ disease at 1 year
• Safety defined as the incidence of ≥ grade 3 toxicities reported as per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0
• Tolerability defined to be the number of patients able to complete therapy as scheduled

Exploratory Outcome Measures:

The scientific research will address the following questions:

1. Do plasma biomarkers for GvHD predict GvHD and non-relapse mortality following T-cell depleted methods of transplantation?
2. Do PTCy methods increase T cell receptor repertoire diversity (as measured by TCR DNA sequencing) compared to ATG-based T cell depletion?
3. How do the different methods of T-cell depletion impact upon donor Treg reconstitution?
4. How do the different methods of T-cell depletion impact upon thymic function as evaluated by measurement of recent thymic emigrants?
5. Are PTCy methods of TCD associated with better preservation of virus-specific immunity (as measured by tetramer or ex vivo functional immune responses)?

Patient Population

Adults considered suitable for an allo-SCT with the following haematological malignancies will be recruited to this trial:

• Acute Myeloid Leukaemia (AML)
• Acute lymphoblastic leukaemia (ALL)
• Chronic myelomonocytic leukemia (CMML)
• Myelodysplastic syndromes (MDS)
• Non-Hodgkin lymphoma (NHL)
• Hodgkin lymphoma (HL)
• Multiple myeloma (MM)
• Chronic lymphocytic leukaemia (CLL)
• Chronic myeloid leukaemia (CML)
• Myelofibrosis

Sample Size:

Up to 400 patients will be randomised to the MoTD trial across IMPACT centres.

Trial Duration:

Patients will be recruited over 48 months. Patients will be followed up for a minimum of 1 year.

MoTD Trials Office Contact Details:

MoTD trials office, Centre for Clinical Haematology, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH Tel: 0121 371 7858 Email: MoTD@trials.bham.ac.uk

Inclusion Criteria:

• Availability of suitably matched unrelated donor (9/10 or 10/10)

• Planned to receive one of the following RIC protocols:

  • Fludarabine-Melphalan (Fludarabine 120-180mg/m2 IV; melphalan ≤ 150mg/m2 IV)
  • BEAM or LEAM (carmustine 300mg/m2 IV or lomustine 200mg/m2 IV with: etoposide 800 mg/m2 IV; cytarabine 1600mg/m2 IV; melphalan 140mg/m2 IV)
  • Fludarabine-Busulphan (Fludarabine 120-180mg/m2 IV; Busulphan ≤ 8mg/kg PO or 6.4mg/kg IV)
  • Fludarabine- Treosulfan (Fludarabine 150mg/m2 IV; Treosulfan 30g/m2 IV)

• Planned use of PBSCs for transplantation

• Planned allo-SCT for one of the following haematological malignancies:

  • AML in CR (patients enrolled onto the COSI trial are not eligible for this study)
  • ALL in CR (patients enrolled onto the ALL-RIC trial are not eligible for this study)
  • CMML <10% blasts
  • MDS <10% blasts (patients enrolled onto the COSI trial are not eligible for this study)
  • NHL in CR/PR
  • HL in CR/PR
  • MM in CR/PR
  • CLL in CR/PR
  • CML in 1st or 2nd chronic phase
  • Myelofibrosis

• Age 16-70 years

• Females of and male patients of reproductive potential (i.e., not post-menopausal or surgically sterilised) must agree to use appropriate, highly effective, contraception from the point of commencing therapy until 12 months after transplant

Exclusion Criteria:

• Use of any method of graft manipulation (excluding storage of future DLI)

• Use of alemtuzumab or any method of T cell depletion except those that are protocol-defined

• Known hypersensitivity to study drugs or history of hypersensitivity to rabbits

• Pregnant or lactating women

• Adults of reproductive potential not willing to use appropriate, highly effective, contraception during the specified period

• Life expectancy <8 weeks

• Active HBV or HCV infection

• Organ dysfunction defined as:

  • LVEF <45%
  • GFR <50ml/min
  • Bilirubin >50µmol/l
  • AST/ALT>3 x ULN

• Participation in COSI or ALL-RIC trials

• Contraindication to treatment with the study drugs (Thymoglobulin, cyclophosphamide, sirolimus, ciclosporin and mycophenolate mofetil) as detailed in each study drug SPC.

• Patient has any other systemic dysfunction (e.g., gastrointestinal, renal, respiratory, cardiovascular) or significant disorder which, in the opinion of the investigator would jeopardise the safety of the patient by taking part in the trial.