A Trial of Treatments to Assess the Effects on Outcome of Adults With AML and MDS Undergoing Allogeneic SCT
- Conditions
- Acute Myeloid LeukaemiaHigh-risk Myelodysplastic Syndrome
- Interventions
- Registration Number
- NCT04217278
- Lead Sponsor
- University of Birmingham
- Brief Summary
Treatment options for older adults with Acute Myeloid Leukaemia (AML) and Myelodysplasia (MDS) are limited. Although stem cell transplantation remains one of the most effective treatments it is associated with severe side effects which have until recently prevented its use in older adults. In the last decade the use of reduced intensity transplants has allowed the extension of the potentially curative effect of transplantation to older patients in whom it was previously precluded. Although a major advance such transplants are associated with a high risk of disease relapse particularly in patients with high risk disease.
This study will evaluate new transplant strategies with the aim of improving the outcome of patients with AML and high risk MDS after stem cell transplantation. Three approaches to improve transplant outcome will be studied:
1. Comparing the new pre-transplant consolidation therapy vyxeos with the standard consolidation therapy (Randomisation 1 is now closed to recruitment).
2. Comparing new conditioning therapies in patients under the age of 55 years
3. Comparing new conditioning therapies in patients aged 55 and over
All patients will be followed up for a minimum of 2 years.
- Detailed Description
This is a randomised, international, phase II/III, multicentre, clinical trial in patients with AML and MDS undergoing allo-SCT. Patients with AML or MDS who fulfil the eligibility criteria will be invited to participate in the trial across centers performing allo-SCT.
Patients will be randomised to treatment based on a minimisation algorithm prepared at the Cancer Research UK Clinical Trials Unit (CRCTU).
Randomisation 1 (R1) (closed to recruitment) will compare the novel consolidation therapy vyxeos with the standard consolidation therapy intermediate dose cytarabine.
Randomisation 2 (R2) will compare the novel conditioning regimen thiotepa/busulphan/fludarabine (TBF) with the standard conditioning therapy fludarabine/busulphan (FB4) in patients aged under 55 years of age.
Randomisation 3 (R3) will compare the novel conditioning regimen mini thiotepa/busulphan/fludarabine (mini TBF) with the standard regimen fludarabine/busulphan (FB2) in patients aged 55 years of age and over (or patients aged under 55 with comorbidities).
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 333
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description R2: FB4 Busulphan Second Randomisation - under 55 years - control arm: Fludarabine (40mg/m\^2 days -7, -6, -5, and -4), Busulphan (3.2mg/kg days -7, -6, -5 and -4) R2: TBF Fludarabine Second Randomisation - under 55 years - experimental arm: Thiotepa (5mg/kg day -7 and -6), Busulphan (3.2mg/kg days -5, -4 and -3), Fludarabine (50mg/m\^2 days -5, -4 and -3) R1: Intermediate dose Cytarabine Cytarabine First Randomisation (closed to recruitment) - control arm: Intermediate dose Cytarabine (1g/m\^2 administered by intravenous infusion over 2 hours on days 1-5 inclusive) Mini-TBF Fludarabine Third Randomisation - 55 years and over (or under 55 with comorbidities) - experimental arm: Thiotepa (5mg/kg day -6), Busulphan (3.2mg/kg days -5 and -4), Fludarabine (50mg/m\^2 days -5, -4, and -3) Mini-TBF Busulphan Third Randomisation - 55 years and over (or under 55 with comorbidities) - experimental arm: Thiotepa (5mg/kg day -6), Busulphan (3.2mg/kg days -5 and -4), Fludarabine (50mg/m\^2 days -5, -4, and -3) Mini-TBF Thiotepa Third Randomisation - 55 years and over (or under 55 with comorbidities) - experimental arm: Thiotepa (5mg/kg day -6), Busulphan (3.2mg/kg days -5 and -4), Fludarabine (50mg/m\^2 days -5, -4, and -3) R2: FB4 Fludarabine Second Randomisation - under 55 years - control arm: Fludarabine (40mg/m\^2 days -7, -6, -5, and -4), Busulphan (3.2mg/kg days -7, -6, -5 and -4) R1: Vyxeos Vyxeos First Randomisation (closed to recruitment) - experimental arm: Vyxeos (29mg/65mg/m\^2 administered by intravenous infusion over 90 minutes on days 1 and 3) R2: TBF Thiotepa Second Randomisation - under 55 years - experimental arm: Thiotepa (5mg/kg day -7 and -6), Busulphan (3.2mg/kg days -5, -4 and -3), Fludarabine (50mg/m\^2 days -5, -4 and -3) R2: TBF Busulphan Second Randomisation - under 55 years - experimental arm: Thiotepa (5mg/kg day -7 and -6), Busulphan (3.2mg/kg days -5, -4 and -3), Fludarabine (50mg/m\^2 days -5, -4 and -3) R3: FB2 Fludarabine Third Randomisation - 55 years and over (or under 55 with comorbidities) - control arm: Fludarabine (30mg/m\^2 days -6, -5, -4, -3 and -2), Busulphan (3.2mg/kg days -6 and -5) R3: FB2 Busulphan Third Randomisation - 55 years and over (or under 55 with comorbidities) - control arm: Fludarabine (30mg/m\^2 days -6, -5, -4, -3 and -2), Busulphan (3.2mg/kg days -6 and -5)
- Primary Outcome Measures
Name Time Method Overall survival (all randomisations) 12 and 24 months Defined as time from entering the relevant randomisation to the relevant question until death from any cause. Patients who are alive at the end of the trial or have been lost to follow up will be censored at their date last seen. For randomisations 2 and 3 this outcome will also be calculated as time from transplantation in order to run a sensitivity analysis.
- Secondary Outcome Measures
Name Time Method Disease-free survival From date of randomisation through to study completion, an average of 6 years DFS defined as time from randomisation to the relevant question to the first of relapse or death from any cause. Patients who are alive and disease free at the end of the trial will be censored at their date known to be alive.
Incidence of primary graft failure - R2 and R3 only From date of randomisation through to study completion, an average of 6 years Defined as loss of donor cells after transplantation - Randomisation 2 and 3 only
Cumulative incidence of disease relapse From date of randomisation through to study completion, an average of 6 years CIR defined as time from randomisation to the relevant question to the date of relapse. Patients who die prior to relapse will be treated as a competing risk and patients who are alive and relapse free at the end of the trial will be censored at their date last seen.
Quality of Life measured by EQ-5D questionnaires, recorded at multiple timepoints - R2 and R3 only Assessed at pre transplant, day 28 and months 3, 6, 9, 12, 18 and 24 EQ5D is one of the most widely used health states descriptive system. EQ-5D questionnaires have 5 dimensions: "Mobility", "Human Autonomy," "Current Activities", "Pain / Discomfort", "Anxiety / Depression" and all dimensions are described by 3 problem levels corresponding to patient response choices. A quality of life score is obtained according to the answers to the questionnaires.
Change in MRD status - R1 only Assessed at baseline and pre-transplant Change in minimal residual disease status. A patient will be categorised as either MRD status reduction (MRD positive to negative), MRD remain negative, MRD remain positive or MRD progression (MRD negative to positive) - Randomisation 1 only
Non-relapse mortality From date of randomisation through to study completion, an average of 6 years NRM defined as the time from randomisation to the relevant question to date of non-relapse death. Patients who die post-relapse will be treated as a competing risk and patients who are alive at the end of the trial will be censored at their date last seen.
Incidence of acute and chronic Graft versus Host Disease - R2 and R3 only From date of randomisation through to study completion, an average of 6 years Incidence of acute and chronic GvHD of any grade - Randomisation 2 and 3 only
Incidence of toxicities reported as per CTCAE V4.0 From start of treatment until 28 days after last dose of treatment Defined as the number of patients who report one or more adverse event of grade 3 or higher or a serious adverse event of any grade
Quality of Life measured by EORTC-QLQ-C30 questionnaires, recorded at multiple timepoints - R2 and R3 only Assessed at pre transplant, day 28 and months 3, 6, 9, 12, 18 and 24 The EORTC QLQ-C30 uses for the questions 1 to 28 a 4-point scale. The scale scores from 1 to 4 ("Not at all" to "Very much"). For the raw score, less points are considered to have a better outcome. For the questions 29 and 30 it uses a 7-points scale. The scale scores from 1 to 7 ("very poor" to "excellent"). More points are considered to have a better outcome.
Trial Locations
- Locations (14)
King's College Hospital
🇬🇧London, United Kingdom
Nottingham City Hospital
🇬🇧Nottingham, United Kingdom
Manchester Royal Infirmary
🇬🇧Manchester, United Kingdom
Queen Elizabeth Hospital Glasgow
🇬🇧Glasgow, United Kingdom
St James' University Hospital
🇬🇧Leeds, United Kingdom
Queen Elizabeth Hospital
🇬🇧Birmingham, United Kingdom
University Hospitals Bristol
🇬🇧Bristol, United Kingdom
Addenbrooke's Hospital
🇬🇧Cambridge, United Kingdom
University Hospital of Wales
🇬🇧Cardiff, United Kingdom
Hammersmith Hospital
🇬🇧London, United Kingdom
Leicester Royal Infirmary
🇬🇧Leicester, United Kingdom
Churchill Hospital
🇬🇧Oxford, United Kingdom
Derriford Hospital
🇬🇧Plymouth, United Kingdom
Freeman Hospital
🇬🇧Newcastle, United Kingdom