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

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.

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).

Eligibility Criteria:
Eligibility Criteria for Randomisation 1 (closed to recruitment) 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:

   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
6. Patients willing and able to comply with scheduled study visits and laboratory tests Exclusion Criteria for Randomisation 1

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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

Eligibility Criteria for Randomisation 2 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: 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
7. Patients willing and able to comply with scheduled study visits and laboratory tests Exclusion Criteria for Randomisation 2

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.

Eligibility Criteria for Randomisation 3 Inclusion Criteria for Randomisation 3 1. 1. Patients aged between 55 years or older with a morphological documented diagnosis of AML or MDS who are deemed fit for a RIC allo-SCT (or under the age of 55 with comorbidities which are deemed by the local investigator to preclude safe delivery of a MAC allo-SCT may be considered per investigators discretion) 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
* 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

* 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 rsk), 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 RIC allo-SCT as clinically judged by the Local Investigator including: a. Adequate hepatic and renal function as determined by full blood count and biochemistry assessment b. Resolution of any toxic effects of prior therapy (including radiotherapy, chemotherapy or surgical procedures) c. 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. Patients willing and able to comply with scheduled study visits and laboratory tests Exclusion Criteria for Randomisation 3

  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.