An international randomised clinical trial of therapeutic interventions with the potential to improve outcome in adults with acute myeloid leukaemia and high-risk myelodysplasia undergoing allogeneic stem cell transplantatio

Phase 2

• Conditions: Acute myeloid leukaemia, myelodysplastic syndromes; Cancer

• Registration Number: ISRCTN12434060
• Lead Sponsor: niversity of Birmingham

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2019-03-20
• Last Update Posted: 17 April 2023
• Study Completion: 2025-03-15

Recruitment & Eligibility

• Status: Ongoing
• Sex: All
• Target Recruitment: 333

Inclusion Criteria

Inclusion Criteria for Randomisation 1:
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:
1.1. AML:
1.1.1. Patients in 1st complete remission (CR1) defined as < 5% blasts
1.1.2. Patients in 2nd complete remission (CR2) defined as < 5% blasts
1.1.3. Secondary AML (defined as previous history of MDS, antecedent haematological disease or chemotherapy
exposure) in CR1 or 2 defined as < 5% blasts
1.2. MDS:
1.2.1 Patients with 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, DRß1 or DQB1 locus)
3. Patients must be considered suitable 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
6. Patients willing and able to comply with scheduled study visits and laboratory tests

Inclusion Criteria for Randomisation 2:
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:
1.1. AML:
1.1.1. Patients in 1st complete remission (CR1) defined as < 5% blasts
1.1.2. Patients in 2nd complete remission (CR2) defined as < 5% blasts
1.1.3. Secondary AML (defined as previous history of MDS, antecedent haematological disease or chemotherapy exposure) in CR1 or 2 defined as < 5% blasts
1.1.4. 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.
1.2. MDS:
1.2.1 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 DRß1, or DQB1 locus)
3. Patients with an ECOG performance status of 0,1 or 2
4. Patients considered suitable to undergo a MAC allo-SCT as clinically judged by the Local Investigator including:
4.1. Adequate hepatic and renal function as determined by full blood count and biochemistry assessment
4.2. Resolution of any toxic effects of prior therapy (including radiotherapy, chemotherapy or surgical procedures)
4.3. 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
7. Patient

Exclusion Criteria

Exclusion criteria for Randomisation 1 (R1):
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

Exclusion criteria for Randomisation 2 (R2):
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 tumour, 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.

Exclusion criteria for Randomisation 3 (R3):
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 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 tumour, 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.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Current primary outcome measure as of 09/12/2022:<br>Overall survival defined as the time from 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<br>transplantation in order to run a sensitivity analysis.<br><br><br><br>Previous primary outcome measure:<br>Overall survival defined as the time from randomisation to 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.