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

NCT ID: NCT04217278

Last Updated: 2023-05-10

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 333 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-01-27
• Study Completion Date: 2025-03-31

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).

Conditions

Acute Myeloid Leukaemia; High-risk Myelodysplastic Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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)

Group Type: ACTIVE_COMPARATOR

Cytarabine

Intervention Type: DRUG

Cytarabine administered by intravenous infusion

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)

Group Type: EXPERIMENTAL

Vyxeos

Intervention Type: DRUG

Vyxeos administered by intravenous infusion

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)

Group Type: ACTIVE_COMPARATOR

Fludarabine

Intervention Type: DRUG

Fludarabine administered by intravenous infusion

Busulphan

Intervention Type: DRUG

Busulphan administered by intravenous infusion

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)

Group Type: EXPERIMENTAL

Fludarabine

Intervention Type: DRUG

Fludarabine administered by intravenous infusion

Busulphan

Intervention Type: DRUG

Busulphan administered by intravenous infusion

Thiotepa

Intervention Type: DRUG

Thiotepa administered by intravenous infusion

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)

Group Type: ACTIVE_COMPARATOR

Fludarabine

Intervention Type: DRUG

Fludarabine administered by intravenous infusion

Busulphan

Intervention Type: DRUG

Busulphan administered by intravenous infusion

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)

Group Type: EXPERIMENTAL

Fludarabine

Intervention Type: DRUG

Fludarabine administered by intravenous infusion

Busulphan

Intervention Type: DRUG

Busulphan administered by intravenous infusion

Thiotepa

Intervention Type: DRUG

Thiotepa administered by intravenous infusion

Interventions

Vyxeos

Vyxeos administered by intravenous infusion

Intervention Type: DRUG

Fludarabine

Fludarabine administered by intravenous infusion

Intervention Type: DRUG

Busulphan

Busulphan administered by intravenous infusion

Intervention Type: DRUG

Thiotepa

Thiotepa administered by intravenous infusion

Intervention Type: DRUG

Cytarabine

Cytarabine administered by intravenous infusion

Intervention Type: DRUG

Other Intervention Names

CPX-351; Fludara; Busulfan; Bulsivex; Tepadina; Ara-C; Cytosine arabinoside

Eligibility Criteria

Inclusion Criteria

1. 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)

2. 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)

3. Patients must be considered suitable/fit to undergo allo-SCT as clinically judged by the Local Investigator

4. 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

5. Patients have given written informed consent

1. 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

2. 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)

3. Patients with an ECOG performance status of 0, 1 or 2

4. Patients considered suitable/fit to undergo a MAC allo-SCT as clinically judged by the Local Investigator including:

1. Adequate hepatic and renal function as determined by full blood count and biochemistry assessment

2. Resolution of any toxic effects of prior therapy (including radiotherapy, chemotherapy or surgical procedures)

3. Performance of cardiac or pulmonary function tests (where there is a previous history of cardiac or pulmonary impairment)

5. 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 12 months after treatment

6. Patients have given written informed consent

• 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

Exclusion Criteria

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1. Patients with contraindications to receiving allo-SCT

2. Female patients who are pregnant or breastfeeding. All women of childbearing potential must have a negative pregnancy test before commencing treatment

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

4. Patients with renal or hepatic impairment as clinically judged by the Local Investigator

5. Patients with active infection, HIV-positive or chronic active HBV or HCV.

6. 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.

7. History of serious hypersensitivity reaction to cytarabine, daunorubicin, or any component of the Vyxeos formulation.

8. Known history of Wilson's disease or other copper-related metabolic disorder since copper gluconate is a component of the Vyxeos formulation

1. Patients with contraindications to receiving a MAC allo-SCT 2. Female patients who are pregnant or breastfeeding. All women of childbearing potential must have a negative pregnancy test before commencing treatment 3. Adults of reproductive potential not willing to use appropriate, effective, contraception during the specified period 4. Patients with renal or hepatic impairment as clinically judged by the Local Investigator 5. Patients with active infection, HIV-positive or chronic active HBV or HCV 6. 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.

1. Patients with contraindications to receiving a RIC allo-SCT

2. Female patients who are pregnant or breastfeeding. All women of childbearing potential must have a negative pregnancy test before commencing treatment

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

4. Patients with renal or hepatic impairment as clinically judged by the Local Investigator

5. Patients with active infection, HIV-positive or chronic active HBV or HCV

6. Patients with a prior malignancies, 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Jazz Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

IMPACT (funded by NHS Blood & Transplant, Anthony Nolan and Leukaemia UK)

UNKNOWN

Sponsor Role: collaborator

Adienne SA

INDUSTRY

Sponsor Role: collaborator

University of Birmingham

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Charles Craddock, Professor

Role: PRINCIPAL_INVESTIGATOR

University Hospital Birmingham NHS Foundation Trust

Locations

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

Queen Elizabeth Hospital Glasgow

Glasgow, , United Kingdom

St James' University Hospital

Leeds, , United Kingdom

Leicester Royal Infirmary

Leicester, , United Kingdom

Hammersmith Hospital

London, , United Kingdom

King's College Hospital

London, , United Kingdom

Manchester Royal Infirmary

Manchester, , United Kingdom

Freeman Hospital

Newcastle, , United Kingdom

Nottingham City Hospital

Nottingham, , United Kingdom

Churchill Hospital

Oxford, , United Kingdom

Derriford Hospital

Plymouth, , United Kingdom

Countries

United Kingdom

Other Identifiers

RG_17-234

Identifier Type: -

Identifier Source: org_study_id