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

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ClinicalTrials.gov Identifier: NCT04217278
Recruitment Status : Recruiting
First Posted : January 3, 2020
Last Update Posted : March 24, 2020
Sponsor:
Information provided by (Responsible Party):
University of Birmingham

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
  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.


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukaemia Myelodysplasia Drug: Vyxeos Drug: Fludarabine Drug: Busulphan Drug: Thiotepa Drug: Cytarabine Phase 3

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) 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 760 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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 Transplantation
Actual Study Start Date : January 27, 2020
Estimated Primary Completion Date : January 2024
Estimated Study Completion Date : January 2026


Arm Intervention/treatment
Active Comparator: R1: Intermediate dose Cytarabine
First Randomisation - control arm: Intermediate dose Cytarabine (1g/m^2 administered by intravenous infusion over 2 hours on days 1-5 inclusive)
Drug: Cytarabine
Cytarabine administered by intravenous infusion
Other Names:
  • Ara-C
  • Cytosine arabinoside

Experimental: R1: Vyxeos
First Randomisation - experimental arm: Vyxeos (29mg/65mg/m^2 administered by intravenous infusion over 90 minutes on days 1 and 3)
Drug: Vyxeos
Vyxeos administered by intravenous infusion
Other Name: CPX-351

Active Comparator: 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)
Drug: Fludarabine
Fludarabine administered by intravenous infusion
Other Name: Fludara

Drug: Busulphan
Busulphan administered by intravenous infusion
Other Names:
  • Busulfan
  • Bulsivex

Experimental: 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)
Drug: Fludarabine
Fludarabine administered by intravenous infusion
Other Name: Fludara

Drug: Busulphan
Busulphan administered by intravenous infusion
Other Names:
  • Busulfan
  • Bulsivex

Drug: Thiotepa
Thiotepa administered by intravenous infusion
Other Name: Tepadina

Active Comparator: R3: FB2
Third Randomisation - 55 years and over - control arm: Fludarabine (30mg/m^2 days -6, -5, -4, -3 and -2), Busulphan (3.2mg/kg days -6 and -5)
Drug: Fludarabine
Fludarabine administered by intravenous infusion
Other Name: Fludara

Drug: Busulphan
Busulphan administered by intravenous infusion
Other Names:
  • Busulfan
  • Bulsivex

Experimental: Mini-TBF
Third Randomisation - 55 years and over - 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
Fludarabine administered by intravenous infusion
Other Name: Fludara

Drug: Busulphan
Busulphan administered by intravenous infusion
Other Names:
  • Busulfan
  • Bulsivex

Drug: Thiotepa
Thiotepa administered by intravenous infusion
Other Name: Tepadina




Primary Outcome Measures :
  1. Overall survival (all randomisations) [ Time Frame: 12 months ]
    Defined as time from entering the relevant randomisations until death from any cause. Patients who are alive at the end of the trial will be censored at their date last seen.


Secondary Outcome Measures :
  1. Change in MRD status - R1 only [ Time Frame: Assessed at baseline and pre-transplant ]
    Change in minimal residual disease status. A patient will be categorised as either MRD status reduction (MRD positive to negative), MRD remain negative, MRD remain positive or MRD progression (MRD negative to positive) - Randomisation 1 only

  2. Disease-free survival [ Time Frame: From date of randomisation through to study completion, an average of 6 years ]
    DFS defined as time from randomisation to the relevant question to the first of relapse or death from any cause. Patients who are alive and disease free at the end of the trial will be censored at their date known to be alive

  3. Cumulative incidence of disease relapse [ Time Frame: From date of randomisation through to study completion, an average of 6 years ]
    CIR defined as time from randomisation to the relevant question to the date of relapse. Patients who die prior to relapse will be treated as a competing risk and patients who are alive and relapse free at the end of the trial will be censored at their date last seen

  4. Non-relapse mortality [ Time Frame: From date of randomisation through to study completion, an average of 6 years ]
    NRM defined as the time from randomisation to the relevant question to date of non-relapse death. Patients who die post-relapse will be treated as a competing risk and patients who are alive at the end of the trial will be censored at their date last seen.

  5. Quality of Life measured by EORTC-QLQ-C30 questionnaires, recorded at multiple timepoints - R2 and R3 only [ Time Frame: Assessed at pre transplant, day 28 and months 3, 6, 9, 12, 18 and 24 ]
    The EORTC QLQ-C30 uses for the questions 1 to 28 a 4-point scale. The scale scores from 1 to 4 ("Not at all" to "Very much"). For the raw score, less points are considered to have a better outcome. For the questions 29 and 30 it uses a 7-points scale. The scale scores from 1 to 7 ("very poor" to "excellent"). More points are considered to have a better outcome.

  6. Quality of Life measured by EQ-5D questionnaires, recorded at multiple timepoints - R2 and R3 only [ Time Frame: Assessed at pre transplant, day 28 and months 3, 6, 9, 12, 18 and 24 ]
    EQ5D is one of the most widely used health states descriptive system. EQ-5D questionnaires have 5 dimensions: "Mobility", "Human Autonomy," "Current Activities", "Pain / Discomfort", "Anxiety / Depression" and all dimensions are described by 3 problem levels corresponding to patient response choices. A quality of life score is obtained according to the answers to the questionnaires.

  7. Incidence of acute and chronic Graft versus Host Disease - R2 and R3 only [ Time Frame: From date of randomisation through to study completion, an average of 6 years ]
    Incidence of acute and chronic GvHD of any grade - Randomisation 2 and 3 only

  8. Incidence of primary graft failure - R2 and R3 only [ Time Frame: From date of randomisation through to study completion, an average of 6 years ]
    Defined as loss of donor cells after transplantation - Randomisation 2 and 3 only

  9. Toxicity reported as per CTCAE V4.0 [ Time Frame: From start of treatment until 28 days after last dose of treatment ]
    Defined as the number of patients who report one or more adverse event of grade 3 or higher or a serious adverse event of any grade



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Eligibility Criteria for Randomisation 1 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

    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 MDS
    • Patients with advanced or high risk MDS with an IPSS-R of ≥3.5 (intermediate 3.5 or higher)
  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 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
  1. Patients with contraindications to receiving allo-SCT
  2. Patients who have already received Vyxeos in their most recent treatment schedule
  3. Female patients who are pregnant or breastfeeding. All women of childbearing potential must have a negative pregnancy test before commencing treatment
  4. Adults of reproductive potential not willing to use appropriate, highly effective, contraception during the specified period
  5. Patients with renal or hepatic impairment as clinically judged by the Local Investigator
  6. Patients with active infection, HIV-positive or chronic active HBV or HCV.
  7. 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. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent < 5 years previously will not be allowed
  8. History of serious hypersensitivity reaction to cytarabine, daunorubicin, or any component of the Vyxeos formulation.
  9. 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

    • 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 MDS
    • Patients with advanced or high risk MDS (with an IPSS-R of ≥3.5 (intermediate 3.5 or higher) 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 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. 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. 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 with one of the following disease characteristics:

    AML o Patients in 1st complete remission (CR1) defined as < 5% blasts

    o Patients in 2nd complete remission (CR2) defined as < 5% blasts

    o Secondary AML (defined as previous history of MDS, antecedent haematological disease or chemotherapy exposure) in CR1 or 2 defined as < 5% blasts

    o Must have received at least two courses of prior intensive chemotherapy prior to transplant unless there are exceptional circumstances MDS

    • Patients with advanced or high risk MDS (with an IPSS-R of ≥3.5 (intermediate 3.5 or higher) 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 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:

    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 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. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent < 5 years previously will not be allowed.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04217278


Contacts
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Contact: Eszter Nagy 00442123717858 COSI@trials.bham.ac.uk

Locations
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United Kingdom
Queen Elizabeth Hospital Recruiting
Birmingham, United Kingdom
Contact: Charles Craddock         
Sponsors and Collaborators
University of Birmingham
Investigators
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Principal Investigator: Charles Craddock University Hospitals Birmingham NHS Foundation Trust
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Responsible Party: University of Birmingham
ClinicalTrials.gov Identifier: NCT04217278    
Other Study ID Numbers: RG_17-234
First Posted: January 3, 2020    Key Record Dates
Last Update Posted: March 24, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Cytarabine
Fludarabine
Busulfan
Thiotepa
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents
Alkylating Agents
Antineoplastic Agents, Alkylating
Myeloablative Agonists