Condition category
Cancer
Date applied
07/01/2021
Date assigned
14/01/2021
Last edited
14/01/2021
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Plain English summary under review with external organization

Background and study aims
Stem cell transplantation from a donor (called ‘allogeneic transplant’) is the only curative therapy for many children and adults with blood cancer. One of the main complications after a transplant is a condition called graft versus host disease (GvHD) which occurs when donor cells (the ‘graft’) see the patient’s (the ‘host’s) normal cells (such as healthy skin, gut or liver) as ‘different’ and attacks them. This can be beneficial as it means that the new immune system is working and is likely to be attacking any remaining or returning disease. This is referred to as ‘graft versus leukaemia’ or ‘graft-versus-tumour’ effect. However, too much GvHD can cause unwanted complications and side effects, including damage to the liver, eyes, mouth, gut, lungs or skin.
Patients currently receive a combination of drugs and antibodies during and after their transplant to prevent GvHD. A number of new approaches have been developed to prevent GvHD from occurring, some of which will be looked at in this trial.
This is a late phase trial composed of three parts (randomisations) which will compare three different treatments:
1. One of the standard UK and European approaches for GvHD prevention using the drugs thymoglobulin, cyclosporine and mycophenolate mofetil (called MMF for short)
2. A new approach using the drugs cyclophosphamide, MMF and cyclosporine
3. A new approach using the drugs cyclophosphamide, MMF and sirolimus
Although there is good evidence from a number of previous studies that the newer approaches may be beneficial in reducing the risk of GvHD compared to other treatment approaches, these have not been compared with the standard approach in the UK. The aim of this trial is to see if the use of these new approaches is better at preventing GvHD occurring compared to the standard approach.

Who can participate?
Patients diagnosed with blood cancer and are being considered to undergo an allogeneic stem cell transplant by their doctor

What does the study involve?
The aim of this trial is to compare the current standard approach for preventing GvHD with two new approaches listed above in order to see if the new approaches are better at reducing the risk of GvHD developing after a transplant. Participating in the study will require receiving treatment while participants are in hospital and having follow-up visits to monitor their response to the treatment and any side-effects they may have. The researchers will ask participants to donate small amounts of samples from routine blood tests for research purposes.

What are the possible benefits and risks of participating?
There is already good evidence that the standard treatment and the two experimental treatments will reduce the risk of GvHD compared to other treatment approaches not being studied in this trial. It is possible that the experimental treatments will have other benefits by allowing the immune system to recover more quickly than the standard treatment so that patients will have a lower risk of infection. It is hoped that this trial will inform the researchers about how to manage such patients in the future.
Like all medicines, the ones used in this trial have side effects. Although all of these drugs are already being routinely used as transplant treatment, the researchers cannot anticipate all of the side effects that participants may experience. They do not know yet whether either of the experimental treatments will be worse, better or the same than the standard treatment and this is the reason they are doing the trial. During the time patients receive treatment they will be monitored regularly for side effects. Participants will be reviewed regularly by the doctor and have blood tests to check for side effects. The toxicities associated with all treatments will be reviewed by an independent Data Monitoring Committee to ensure that there is no excessive toxicity observed in the experimental arms.

Where is the study run from?
The Cancer Research Clinical Trials Unit at the University of Birmingham (UK)

When is the study starting and how long is it expected to run for?
January 2019 to June 2025

Who is funding the study?
The trial is funded through the IMPACT network which is funded by Anthony Nolan, Leuka and NHS Blood Transplant (UK)

Who is the main contact?
Dr Andrea Hodgkinson
a.hodgkinson@bham.ac.uk
MoTD@trials.bham.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Prof Ronjon Chakraverty

ORCID ID

http://orcid.org/0000-0003-2301-2664

Contact details

Chief Investigator
University College London
Department of Haematology
Pond Street
London
NW3 2QG
United Kingdom
+44 (0)2077940500
ronjon.chakraverty@ndcls.ox.ac.uk

Type

Scientific

Additional contact

Dr Andrea Hodgkinson

ORCID ID

Contact details

CRCTU
Centre for Clinical Haematology
Queen Elizabeth Hospital
Edgbaston
Birmingham
B15 2TH
United Kingdom
+44 (0)121 371 4365
a.hodgkinson@bham.ac.uk

Type

Scientific

Additional contact

Dr Mohamed Elhaneid

ORCID ID

Contact details

CRCTU
Centre for Clinical Haematology
Queen Elizabeth Hospital
Edgbaston
Birmingham
B15 2TH
United Kingdom
+44 (0)121 371 4365
M.A.Elhaneid@bham.ac.uk

Type

Scientific

Additional contact

Mr John Mason

ORCID ID

Contact details

Cancer Research UK Clinical Trials Unit
University of Birmingham
Birmingham
B15 2TT
United Kingdom
+44 (0)121 371 4365
j.a.e.mason@bham.ac.uk

Additional identifiers

EudraCT number

2019-002419-24

ClinicalTrials.gov number

Nil known

Protocol/serial number

CPMS 46327, IRAS 268363

Study information

Scientific title

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

Acronym

MoTD

Study hypothesis

GvHD remains a major cause of morbidity and mortality in patients who have undergone an allo-SCT particularly in patients undergoing unrelated donor allo-SCT. Although T cell depletion with ATG has been shown to be effective in preventing GvHD, its use is still complicated by poor immune reconstitution. By inducing selective in vivo T cell depletion, PTCy may prevent GvHD but allow earlier immune reconstitution. The proposed trial therefore addresses a major unmet need and has the potential to change clinical practice if either of two experimental PTCy strategies is superior to Thymoglobulin.

Ethics approval

Approved 11/09/2020, West Midlands - Edgbaston Research Ethics Committee (3rd Floor Barlow House, Minshull Street, Manchester, M1 3DZ, UK; +44 (0)207 104 8089; edgbaston.rec@hra.nhs.uk), REC ref: 20/WM/0195

Study design

Randomized; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please contact the MoTD trials office if you require a copy using the following email address: MoTD@trials.bham.ac.uk

Condition

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

Intervention

A prospective, multi-centre phase II randomised controlled study using a ‘pick a winner’ approach was chosen to compare two experimental arms to a control arm. The design is adaptive, using two interim analyses. The first, conducted when 150 patients have data up to 100 days, will allow early termination of arms that are clearly inferior based on 100-day severe graft-versus-host-disease (GvHD). The second, conducted when 300 patients have been recruited, will terminate the worst-performing arm, allowing either conclusion of the trial (if standard care is the worst arm), or allocation of the final 100 patients to standard of care and the best-performing experimental arm.

Up to 22 hospitals have been invited to participate in this trial. Patients considered suitable for an allo-SCT with the following haematological malignancies will be invited to participate: acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myelomonocytic leukaemia (CMML), myelodysplastic syndromes (MDS), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), multiple myeloma (MM), chronic lymphocytic leukaemia (CLL), chronic myeloid leukaemia (CML), myelofibrosis.

All patients have the opportunity to discuss transplantation and its long term implications as part of their normal consent process to undergo an NHS clinical procedure. If it is appropriate, Investigators will discuss the trial with patients at this stage and provide them with a trial-specific Patient Information Sheet.

As part of their routine care, patients must undergo screening tests prior to transplantation in order to assess overall health and organ function and ensure that they are suitable to undergo the high-risk procedure of transplantation. These tests are conducted as part of routine transplant workup care and are not required as part of the trial protocol.

All patients will be randomised prior to being admitted to undergo transplantation and will receive a combination of chemotherapy and immunosuppression depending on which treatment arm they are allocated to. Due to the high doses of drugs used during transplantation, patients are admitted as inpatients and monitored closely by the clinical team by regular blood tests and monitoring of vital signs. All adverse events will also be monitored closely by the clinical team.

After patients receive the transplant chemotherapy, they will receive the donated cells from their donor (Day 0). Patients will then continue to receive the allocated GvHD prophylaxis treatments as defined in the protocol. Patients will continue to be monitored closely while their symptoms recover and severe adverse events will be reported to the Trials Office for up to 28 days after the last dose of trial Investigational Medicinal Product (IMP). Patients will continue to be monitored in accordance with their local hospital's practice, and trial assessments will be performed at intervals considered appropriate for the monitoring of transplant outcome as outlined in the protocol.

Patients will be monitored for the duration of the study for symptoms of GvHD which may become a serious complication after transplantation. In addition, unexpected serious adverse events will also be monitored for the duration of the trial. Disease assessment will be performed as per local practice and as appropriate for the patient's disease.

Patients will have regular blood tests during treatment; daily during and for a week after transplant, weekly for the first month after transplant and then at regular intervals until they stop treatment (for safety monitoring). This is consistent with routine monitoring of patients after a transplant. Blood samples will also be collected for research studies at days 7, 28, 56 and 100, and at months 6, 9 and 12 post-transplant. To minimise discomfort to patients all except the day 56 sample will be collected at the same time as routine bloods.

Transplantation often has a significant impact on the quality of life of patients and therefore we will ask patients to complete quality of life questionnaires prior to their transplant and then at months 6 and 12 in order to determine whether there is a difference in the quality of life of patients between the treatment arms.

Patients will complete the trial at the end of 12 months. All data will be collected and analysed centrally at the Trials Office and the study findings will be required in a peer-reviewed medical journal.

Intervention type

Drug

Phase

Phase II

Drug names

Thymoglobulin, cyclosporine, mycophenolate mofetil, cyclophosphamide, sirolimus

Primary outcome measure

GvHD-free, relapse-free survival at 1 year. GVHD assessment scoring will be performed as per the modified Glucksberg criteria (revised by MAGIC) and the National Institutes of Health (NIH) criteria. GvHD-free, relapse-free survival (GRFS) defined as the time from date of day 0 (defined as the day of stem cell infusion) to the date of first event or death from any cause. An event is defined as GvHD (both acute and chronic), relapse or progression. Patients who are alive and event-free at the end of the trial will be censored at their date of last follow-up.

Secondary outcome measures

1. Cumulative incidence of acute grade II-IV and III-IV GvHD measured using the modified Glucksberg criteria (revised by MAGIC) and the National Institutes of Health (NIH) criteria at 1 year
2. Cumulative incidence of moderate and severe chronic GvHD measured using the modified Glucksberg criteria (revised by MAGIC) and the National Institutes of Health (NIH) criteria at 1 year
3. Cumulative incidence of NRM at 1 year. Non-relapse mortality (NRM) is defined as the time from day 0 to date of non-relapse death. Patients who die post-relapse from any other cause will be considered a competing risk and patients alive at the end of the trial will be censored at their date last seen.
4. Overall survival at 1 year. Overall survival (OS) is defined as the time from day 0 to date of death, from any cause. Patients who are alive at the end of the trial will be censored at their date last seen.
5. Progression-free survival at 1 year. Progression-free survival (PFS) is defined as the time from day 0 to date of first relapse/progression or death from any cause. Patients who are alive and progression-free at the end of the trial will be censored at their date last seen.
6. Immune suppression-free survival at 1 year. Immune suppression-free survival is defined as the time from day 0 to the date of first immunosuppressive agent use. Patients who are alive and immune suppression free at the end of the trial will be censored at their date last seen.
7. Cumulative incidence of engraftment measured by blood sample at 1 year. Cumulative incidence of engraftment defined as the time from day 0 to date of engraftment (neutrophil engraftment defined to be the first of 3 consecutive days a neutrophil count ≥0.5 × 10^9/l is reached and platelet engraftment defined to be the first of 3 consecutive days an unsupported platelet count ≥20 × 10^9/l is reached). Patients who relapse/progress or die prior to relapse, progression or engraftment will be considered a competing risk at their date of relapse/progression for the former and date of death for the latter. Patients alive and engraftment free at the end of the trial will be censored at their date last seen.
8. The incidence of full donor chimerism measured by blood sample at 100 days. Engraftment will be assessed by lineage-specific chimerism measurements. Lineage-specific chimerism in both whole blood and T-cell compartments (where possible) will be assessed as per local procedure, performed at 3 monthly intervals for the first 12 months post-transplant; at day 100 and then months 6, 9 and 12. Tests should be performed in local laboratories.
9. The cumulative incidence of infection requiring inpatient admission measured by blood test and tissue culture at 1 year
10. The number of inpatient days measured using sum of inpatients days during the first 12 months
11. The timing and dose of donor lymphocyte infusion (DLI) for mixed chimerism, persistent disease or relapse, collected whenever required for mixed chimerism, persistent disease or relapse
12. Cumulative incidence of EBV-related PTLD measured by blood sample, EBV PCR testing, sites will follow their local policy
13. The number of doses of rituximab administered for EBV reactivation during the first 12 months, collected every time the patient receives it whenever there is EBV reactivation
14. QoL measured by FACT-BMT questionnaire at baseline, 6 months and 12 months
15. Cumulative incidence of patients with haemorrhagic cystitis measured by blood and urine sample at 1 year
16. Cumulative incidence of CMV viremia and CMV end-organ disease measured by blood sample at 1 year
17. 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. Details of all AEs will be documented and reported from the date of commencement of protocol-defined treatment until 28 days after the administration of the last dose of IMP. Serious AEs will be reported from the date of consent.
18. Tolerability defined as the number of patients able to complete therapy as scheduled, excluding any patients who discontinued treatment due to toxicities

Overall trial start date

01/01/2019

Overall trial end date

01/06/2025

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Availability of suitably matched unrelated donor (9/10 or 10/10)
2. Planned to receive one of the following reduced-intensity conditioning (RIC) protocols:
2.1. Fludarabine-melphalan (fludarabine 120-180 mg/m²; melphalan ≤150 mg/m²)
2.2. BEAM or LEAM (carmustine 300 mg/m² or lomustine 200mg/m² with: etoposide 800 mg/m²; cytarabine 1600 mg/m²; melphalan 140 mg/m²)
2.3. Fludarabine-busulphan (fludarabine 120-180 mg/m²; Busulphan ≤8 mg/kg PO or 6.4 mg/kg IV)
3. Planned use of peripheral blood stem cells (PBSCs) for transplantation
4. Planned allo-SCT for one of the following haematological malignancies:
4.1. AML in complete remission (CR)
4.2. ALL in CR
4.3. CMML <10% blasts
4.4. MDS <10% blasts
4.5. NHL in CR/partial remission (PR)
4.6. HL in CR/PR
4.7. MM in CR/PR
4.8. CLL in CR/PR
4.9. CML in 1st or 2nd chronic phase
4.10. Myelofibrosis
5. Age 16-70 years
6. 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

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 400; UK Sample Size: 400

Participant exclusion criteria

1. Use of any method of graft manipulation (excluding storage of future donor lymphocyte infusion)
2. Use of alemtuzumab or any method of T-cell depletion except those that are protocol-defined
3. Known hypersensitivity to study drugs or history of hypersensitivity to rabbits
4. Pregnant or lactating women
5. Adults of reproductive potential not willing to use appropriate, highly effective, contraception during the specified period
6. Life expectancy <8 weeks
7. Active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection
8. Organ dysfunction defined as:
8.1. Left ventricular ejection fraction (LVEF) <45%
8.2. Glomerular filtration rate (GFR) <50 ml/min
8.3. Bilirubin >50 µmol/l
8.4. Aspartate transaminase (AST) or alanine transferase (ALT) >3 x upper limit of normal (ULN)
9. Participation in COSI or ALL-RIC trials

Recruitment start date

15/02/2021

Recruitment end date

30/12/2024

Locations

Countries of recruitment

United Kingdom

Trial participating centre

NHS Greater Glasgow and Clyde
J B Russell House Gartnavel Royal Hospital 1055 Great Western Road
Glasgow
G12 0XH
United Kingdom

Trial participating centre

King's College Hospital NHS Foundation Trust
Denmark Hill
London
SE5 9RS
United Kingdom

Trial participating centre

Leeds Teaching Hospitals NHS Trust
St. James's University Hospital Beckett Street
Leeds
LS9 7TF
United Kingdom

Trial participating centre

Manchester University NHS Foundation Trust
Cobbett House Oxford Road
Manchester
M13 9WL
United Kingdom

Trial participating centre

The Newcastle upon Tyne Hospitals NHS Foundation Trust
Freeman Hospital Freeman Road High Heaton
Newcastle-Upon-Tyne
NE7 7DN
United Kingdom

Trial participating centre

University Hospitals Birmingham NHS Foundation Trust
Trust HQ, PO Box 9551 Queen Elizabeth Medical Centre Edgbaston
Birmingham
B15 2TH
United Kingdom

Trial participating centre

Barts Health NHS Trust
The Royal London Hospital Whitechapel
London
E1 1BB
United Kingdom

Trial participating centre

University Hospitals Bristol NHS Foundation Trust
Marlborough Street
Bristol
BS1 3NU
United Kingdom

Trial participating centre

University College London Hospitals NHS Foundation Trust
250 Euston Road
London
NW1 2PG
United Kingdom

Trial participating centre

Cardiff & Vale University LHB
Corporate Headquarters Heath Park
Cardiff
CF14 4XW
United Kingdom

Trial participating centre

The Christie NHS Foundation Trust
550 Wilmslow Road Withington
Manchester
M20 4BX
United Kingdom

Trial participating centre

Imperial College Healthcare NHS Trust
St. Marys Hospital Praed Street
London
W2 1NY
United Kingdom

Trial participating centre

University Hospitals of Leicester NHS Trust
Leicester Royal Infirmary Infirmary Square
Leicester
LE1 5WW
United Kingdom

Trial participating centre

The Clatterbridge Cancer Centre NHS Foundation Trust
Clatterbridge Road
Bebington
CH63 4JY
United Kingdom

Trial participating centre

Nottingham University Hospitals NHS Trust
Trust Headquarters Queens Medical Centre Derby Road
Nottingham
NG7 2UH
United Kingdom

Trial participating centre

University Hospitals Plymouth NHS Trust
Derriford Hospital Derriford Road
Plymouth
PL6 8DH
United Kingdom

Trial participating centre

Sheffield Teaching Hospitals NHS Foundation Trust
Northern General Hospital Herries Road
Sheffield
S5 7AU
United Kingdom

Trial participating centre

University Hospitals Birmingham NHS Foundation Trust
Queen Elizabeth Hospital Mindelsohn Way Edgbaston
Birmingham
B15 2GW
United Kingdom

Sponsor information

Organisation

University of Birmingham

Sponsor details

c/o Dr Birgit Whitman
Head of Research Governance and Integrity
Research Support Group
University of Birmingham
Aston Webb Building
Room 117
Edgbaston
Birmingham
B15 2TT
United Kingdom
+44 (0)1214158011
Researchgovernance@contacts.bham.ac.uk

Sponsor type

University/education

Website

http://www.birmingham.ac.uk/index.aspx

Funders

Funder type

Charity

Funder name

Leukaemia UK

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

Trusts, charities, foundations (both public and private)

Location

United Kingdom

Results and Publications

Publication and dissemination plan

1. If people want a copy of the protocol they can get in touch with the trial's office email: MoTD@trials.bham.ac.uk
2. Planned publication in a high-impact peer-reviewed journal

IPD sharing statement
The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication

Intention to publish date

01/06/2026

Participant level data

Other

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

14/01/2021: Uploaded protocol Version 2.0, 08 September 2020 (not peer reviewed). 07/01/2021: Trial's existence confirmed by the NIHR.