An International Randomised Clinical Trial of Therapeutic Interventions to Assess the Effects on Outcome in Adults With Acute Myeloid Leukaemia and High Risk Myelodysplasia Undergoing Allogeneic Stem Cell Transplantation.
Trial Snapshot
- Phase
- Phase 2
- Status
- Active, not recruiting
- Sponsor
- University of Birmingham
- Enrollment
- 333
- Locations
- 14
- Primary Endpoint
- Overall survival (all randomisations)
Study Overview
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:
- Comparing the new pre-transplant consolidation therapy vyxeos with the standard consolidation therapy (Randomisation 1 is now closed to recruitment).
- Comparing new conditioning therapies in patients under the age of 55 years
- 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).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
R1: Intermediate dose 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)
Intervention: Cytarabine (Drug)
R2: FB4
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)
Intervention: Fludarabine (Drug)
R2: FB4
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)
Intervention: Busulphan (Drug)
R2: TBF
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)
Intervention: Fludarabine (Drug)
R2: TBF
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)
Intervention: Busulphan (Drug)
R2: TBF
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)
Intervention: Thiotepa (Drug)
R3: FB2
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)
Intervention: Fludarabine (Drug)
R3: FB2
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)
Intervention: Busulphan (Drug)
Mini-TBF
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)
Intervention: Fludarabine (Drug)
Mini-TBF
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)
Intervention: Busulphan (Drug)
Mini-TBF
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)
Intervention: Thiotepa (Drug)
R1: 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)
Intervention: Vyxeos (Drug)
Outcomes
Primary Outcomes
Overall survival (all randomisations)
Time Frame: 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 Outcomes
- Disease-free survival(From date of randomisation through to study completion, an average of 6 years)
- Incidence of primary graft failure - R2 and R3 only(From date of randomisation through to study completion, an average of 6 years)
- Cumulative incidence of disease relapse(From date of randomisation through to study completion, an average of 6 years)
- 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)
- Change in MRD status - R1 only(Assessed at baseline and pre-transplant)
- Non-relapse mortality(From date of randomisation through to study completion, an average of 6 years)
- 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 toxicities reported as per CTCAE V4.0(From start of treatment until 28 days after last dose of treatment)
- 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)