A Trial of Treatments to Assess the Effects on Outcome of Adults With AML and MDS Undergoing Allogeneic SCT

NCT04217278 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: RG_17-234
• Study Type: interventional
• Target: 333
• Locations: 1 country
• Sites: 14

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. 1.Comparing the new pre-transplant consolidation therapy vyxeos with the standard consolidation therapy (Randomisation 1 is now closed to recruitment).
2. 2.Comparing new conditioning therapies in patients under the age of 55 years
3. 3.Comparing new conditioning therapies in patients aged 55 and over

Conditions

Acute Myeloid Leukaemia; High-risk Myelodysplastic Syndrome

Keywords

Allogeneic Stem Cell Transplant; AML; MDS

Outcome Measures

Primary Outcomes (1)

• Overall survival (all randomisations)

  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.

  12 and 24 months

Secondary Outcomes (9)

• Change in MRD status - R1 only

  Assessed at baseline and pre-transplant

• Disease-free survival

  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

• Non-relapse mortality

  From date of randomisation through to study completion, an average of 6 years

• 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

Study Arms (6)

R1: Intermediate dose Cytarabine

ACTIVE COMPARATOR

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)

Drug: Cytarabine

R1: Vyxeos

EXPERIMENTAL

First Randomisation (closed to recruitment) - experimental arm: Vyxeos (29mg/65mg/m\^2 administered by intravenous infusion over 90 minutes on days 1 and 3)

Drug: Vyxeos

R2: FB4

ACTIVE COMPARATOR

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)

Drug: Fludarabine; Drug: Busulphan

R2: TBF

EXPERIMENTAL

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)

Drug: Fludarabine; Drug: Busulphan; Drug: Thiotepa

R3: FB2

ACTIVE COMPARATOR

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)

Drug: Fludarabine; Drug: Busulphan

Mini-TBF

EXPERIMENTAL

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)

Drug: Fludarabine; Drug: Busulphan; Drug: Thiotepa

Interventions

Vyxeos DRUG

Vyxeos administered by intravenous infusion

Also known as: CPX-351

R1: Vyxeos

Fludarabine DRUG

Fludarabine administered by intravenous infusion

Also known as: Fludara

Mini-TBF; R2: FB4; R2: TBF; R3: FB2

Busulphan DRUG

Busulphan administered by intravenous infusion

Also known as: Busulfan, Bulsivex

Mini-TBF; R2: FB4; R2: TBF; R3: FB2

Thiotepa DRUG

Thiotepa administered by intravenous infusion

Also known as: Tepadina

Mini-TBF; R2: TBF

Cytarabine DRUG

Cytarabine administered by intravenous infusion

Also known as: Ara-C, Cytosine arabinoside

R1: Intermediate dose Cytarabine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients (≥ 18 years old) with a morphological documented diagnosis of AML or MDS who are deemed fit for allo-SCT with one of the following disease characteristics:
• AML
• Patients in 1st complete remission (CR1) defined as \< 5% blasts
• Patients in 2nd complete remission (CR2) defined as \< 5% blasts
• Secondary AML (defined as previous history of MDS, antecedent haematological disease or chemotherapy exposure) in CR1 or 2 defined as \< 5% blasts MDS
• Patients with advanced or high risk MDS with an IPSS-R of ≥3.5 (intermediate 3.5 or higher) including intermediate or high risk CMML (e.g. CPSS int-2 or high risk)
• Patients with an identified HLA identical sibling or suitable matched unrelated donor (suitable match defined as no greater than a single allele mismatch at HLA-A, -B, -C, DQB1 or DRβ1)
• Patients must be considered suitable/fit to undergo allo-SCT as clinically judged by the Local Investigator
• Females of and male patients of reproductive potential (i.e., not post-menopausal or surgically sterilised) must use appropriate, highly effective, contraception from the point of commencing therapy until 6 months after treatment
• Patients have given written informed consent

You may not qualify if:

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• Patients with contraindications to receiving allo-SCT
• Female patients who are pregnant or breastfeeding. All women of childbearing potential must have a negative pregnancy test before commencing treatment
• Adults of reproductive potential not willing to use appropriate, highly effective, contraception during the specified period
• Patients with renal or hepatic impairment as clinically judged by the Local Investigator
• Patients with active infection, HIV-positive or chronic active HBV or HCV.
• Patients with a prior malignancy, except lobular breast carcinoma in situ, fully resected basal cell or squamous cell carcinoma of skin or treated cervical carcinoma in situ, incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis (TNM) clinical staging system), previous MDS, CMML, MPN resulting in secondary AML. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent \< 5 years previously will not be allowed.
• History of serious hypersensitivity reaction to cytarabine, daunorubicin, or any component of the Vyxeos formulation.
• Known history of Wilson's disease or other copper-related metabolic disorder since copper gluconate is a component of the Vyxeos formulation
• Patients aged between 18 - 54 years with a morphological documented diagnosis of AML or MDS who are deemed fit for a MAC allo-SCT with one of the following disease characteristics: AML o Patients in 1st complete remission (CR1) defined as \< 5% blasts
• Patients in 2nd complete remission (CR2) defined as \< 5% blasts
• Secondary AML (defined as previous history of MDS, antecedent haematological disease or chemotherapy exposure) in CR1 or 2 defined as \< 5% blasts
• Must have received at least two courses of prior intensive chemotherapy prior to transplant unless there are exceptional circumstances. Patients with AML who have achieved CR with Venetoclax based induction regimen treatment as only prior treatment, will also be eligible.
• MDS
• o Patients with advanced or high risk MDS (with an IPSS-R of ≥3.5 (intermediate 3.5 or higher) including intermediate or high risk CMML (e.g. CPSS int-2 or high risk), who have \< 10% blasts at the time of randomisation following intensive chemotherapy (including R1 randomisation) or hypomethylating agents if necessary

Sponsors & Collaborators

• University of Birmingham: lead
• Jazz Pharmaceuticals: collaborator
• Adienne SA: collaborator

Study Sites (14)

Queen Elizabeth Hospital

Birmingham, United Kingdom

Location

University Hospitals Bristol

Bristol, United Kingdom

Location

Addenbrooke's Hospital

Cambridge, United Kingdom

Location

University Hospital of Wales

Cardiff, United Kingdom

Location

Queen Elizabeth Hospital Glasgow

Glasgow, United Kingdom

Location

St James' University Hospital

Leeds, United Kingdom

Location

Leicester Royal Infirmary

Leicester, United Kingdom

Location

Hammersmith Hospital

London, United Kingdom

Location

King's College Hospital

London, United Kingdom

Location

Manchester Royal Infirmary

Manchester, United Kingdom

Location

Freeman Hospital

Newcastle, United Kingdom

Location

Nottingham City Hospital

Nottingham, United Kingdom

Location

Churchill Hospital

Oxford, United Kingdom

Location

Derriford Hospital

Plymouth, United Kingdom

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

CPX-351; fludarabine; fludarabine phosphate; Busulfan; Thiotepa; Cytarabine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Phosphoramides; Organophosphorus Compounds; Triethylenephosphoramide; Aziridines; Azirines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Charles Craddock, Professor

  University Hospital Birmingham NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 20, 2019
• First Posted: January 3, 2020
• Study Start: January 27, 2020
• Primary Completion: May 1, 2026
• Study Completion: May 1, 2026
• Last Updated: May 5, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (14)