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
| ISRCTN | ISRCTN12434060 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN12434060 |
| EudraCT/CTIS number | 2017-004801-42 |
| IRAS number | 252254 |
| ClinicalTrials.gov number | NCT04217278 |
| Secondary identifying numbers | CPMS 41409, IRAS 252254 |
- Submission date
- 18/03/2019
- Registration date
- 20/03/2019
- Last edited
- 03/04/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Record updated in last year
Plain English summary of protocol
Contact information
Dr Cosi trials
Scientific
Scientific
Haematology Team – IMPACT
Room 15
Centre for Clinical Haematology
Queen Elizabeth Hospital
Edgbaston
Birmingham
B15 2TH
United Kingdom
| Phone | +44 (0)121 371 7859 |
|---|---|
| Cosi@trials.bham.ac.uk |
Study information
| Study design | Randomised; Interventional; Design type: Treatment, Drug |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific 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 |
| Study acronym | COSI |
| Study objectives | The aim of the study is to evaluate new pre-transplant and transplant strategies to improve the outcome of patients allografted for AML or high-risk MDS. |
| Ethics approval(s) | Approved 16/05/2019, North West - Liverpool Central Research Ethics Committee, 3rd Floor, Barlow House, 4 Minshull Street, Manchester, M1 3DZ, Tel: +44 (0)207 104 8196, Email: liverpoolcentral.rec@hra.nhs.uk, ref: 19/NW/0135 |
| Health condition(s) or problem(s) studied | Acute myeloid leukaemia, myelodysplastic syndromes |
| Intervention | There are three separate randomisations in this trial. Randomisation 1 (R1) - patients will be randomised 1:1 to either the experimental arm (Vyxeos pre-transplant consolidation therapy) or the control arm (Intermediate dose cytarabine pre-transplant consolidation therapy). In the control arm patients will receive up to 2 cycles of cytarabine administered as a 2-hour infusion at a dose of 1 g/m2 on days 1-5 of each cycle. In the experimental arm patients will receive up to 2 cycles of Vyxeos administered intravenously over 90 minutes at a dose of 29 mg/65mg/m² on days 1 and 3 of each cycle. Randomisation 2 (R2) - patients aged under 55 years will be randomised 1:1 to either the experimental arm (novel myeloablative conditioning regimen TBF) or the control arm (standard myeloablative conditioning regimen FB4). Patients will receive the allocated myeloablative conditioning regimen in hospital immediately prior to allogeneic stem cell transplant. Randomisation 3 (R3) - patients aged 55 years and over will be randomised 1:1:1 to either one of the two experimental arms (novel reduced intensity conditioning regimen mini TBF or mini FLAMSA-BU) or the control arm (standard reduced intensity conditioning regimen FB2). Patients will receive the allocated reduced-intensity conditioning regimen in hospital immediately prior to allogeneic stem cell transplant. Patients can be randomised to just one of the above randomisations, or can be randomised twice (e.g. R1 and R2 or R1 and R3). All patients will be followed up for 2 years. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase II/III |
| Drug / device / biological / vaccine name(s) | Liposomal cytarabine-daunorubicin (Vyxeos), cytarabine, fludarabine, busulphan, thiotepa |
| Primary outcome measure | Current primary outcome measure as of 09/12/2022: 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 transplantation in order to run a sensitivity analysis. Previous primary outcome measure: 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. |
| Secondary outcome measures | Current secondary outcome measure as of 09/12/2022: 1. Measurable residual disease (MRD) status, collected on randomisation and then again immediately prior to transplant. 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 (closed to recruitment). 2. Disease-free survival defined as time from randomisation to the relevant question to the date of first 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 last known to be alive. 3. Cumulative incidence of disease relapse 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 defined as the time from randomisation 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 and EQ-5D questionnaires pre transplant, at day 28 and months 3, 6, 9, 12, 18 and 24 – Randomisations 2 and 3 only 6. Incidence of acute and chronic GVHD of any grade – Randomisations 2 and 3 only 7. Incidence of primary graft failure – Randomisations 2 and 3 only 8. Incidence of toxicities reported as per CTCAE V4.0 defined as the number of patients who report one or more AE of grade 3 or higher or an SAE of any grade Previous secondary outcome measure: 1. Measurable residual disease (MRD) status, collected on randomisation and then again immediately prior to transplant. 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 defined as time from randomisation to the relevant question to the date of first 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 last known to be alive 3. Cumulative incidence of disease relapse 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 defined as the time from randomisation 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 and EQ-5D questionnaires pre transplant, at day 28 and months 3, 6, 9, 12, 18 and 24 – Randomisations 2 and 3 only 6. Incidence of acute and chronic GVHD of any grade – Randomisations 2 and 3 only 7. Incidence of primary graft failure – Randomisations 2 and 3 only 8. Incidence of toxicities reported as per CTCAE V4.0 defined as the number of patients who report one or more AE of grade 3 or higher or an SAE of any grade |
| Overall study start date | 07/07/2017 |
| Completion date | 15/03/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 394; UK Sample Size: 394 |
| Total final enrolment | 333 |
| Key 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, DRβ1 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 DRβ1, 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. Patients willing and able to comply with scheduled study visits and laboratory tests 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 (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: 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 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,DRβ1 or DQB1 locus) 3. Patients with an ECOG performance status of 0,1 or 2 4. Patients considered suitable 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 |
| Key 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. |
| Date of first enrolment | 27/01/2020 |
| Date of final enrolment | 03/03/2023 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
King's College Hospital
London
SE5 9RS
United Kingdom
SE5 9RS
United Kingdom
St James's University Hospital
Leeds
LS9 7TF
United Kingdom
LS9 7TF
United Kingdom
Manchester Royal Infirmary
Manchester
M13 9WL
United Kingdom
M13 9WL
United Kingdom
Freeman Hospital
Newcastle-Upon-Tyne
NE7 7DN
United Kingdom
NE7 7DN
United Kingdom
Churchill Hospital
Oxford
OX3 7LE
United Kingdom
OX3 7LE
United Kingdom
Queen Elizabeth Hospital
Birmingham
B15 2GW
United Kingdom
B15 2GW
United Kingdom
Bristol Haematology and Oncology Centre
Bristol
BS2 8ED
United Kingdom
BS2 8ED
United Kingdom
Addenbrookes Hospital
Cambridge
CB2 0QQ
United Kingdom
CB2 0QQ
United Kingdom
University Hospital of Wales
Cardiff
CF14 4XW
United Kingdom
CF14 4XW
United Kingdom
Hammersmith Hospital
London
W12 0HS
United Kingdom
W12 0HS
United Kingdom
Leicester Royal Infirmary
Leicester
LE1 5WW
United Kingdom
LE1 5WW
United Kingdom
Nottingham City Hospital
Nottingham
NG5 1PB
United Kingdom
NG5 1PB
United Kingdom
Derriford Hospital
Plymouth
PL6 8DH
United Kingdom
PL6 8DH
United Kingdom
Royal Hallamshire Hospital
Sheffield
S5 7AU
United Kingdom
S5 7AU
United Kingdom
Southampton General Hospital
Southampton
SO16 6YD
United Kingdom
SO16 6YD
United Kingdom
Royal Stoke University Hospital
Stoke-on-Trent
ST4 6QG
United Kingdom
ST4 6QG
United Kingdom
ASST Papa Giovanni XXIII
BERGAMO
24127
Italy
24127
Italy
Sponsor information
University of Birmingham
University/education
University/education
Research Support Group
Aston Webb Building
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
| Phone | +44 (0)121 371 7858 |
|---|---|
| cosi@trials.bham.ac.uk | |
"ROR" |
https://ror.org/03angcq70 |
Funders
Funder type
Charity
IMPACT (funded by NHS Blood & Transplant, Anthony Nolan and Leukaemia UK)
No information available
Jazz Pharmaceuticals
Government organisation / For-profit companies (industry)
Government organisation / For-profit companies (industry)
- Alternative name(s)
- Jazz Pharmaceuticals plc, Greenwich Biosciences, Jazz Pharmaceuticals, Inc.
- Location
- Ireland
ADIENNE SA
No information available
Results and Publications
| Intention to publish date | 01/06/2027 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal |
| IPD sharing plan | The data sharing plans for the current study are unknown and will be made available at a later date. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
03/04/2023: The following changes were made to the trial record:
1. The overall end date was changed from 01/06/2025 to 15/03/2025.
2. The recruitment end date was changed from 27/01/2024 to 03/03/2023.
3. The changes to the interventions, inclusion criteria, and exclusion criteria were removed as they indicated that some phases were closed to recruitment, now all phases are closed to recruitment.
09/12/2022: The following changes have been made:
1. ClinicalTrials.gov number was added.
2. IRAS number was added.
3. Ethics approval was updated.
4. The overall trial end date was changed from 01/06/2025 to 27/01/2027.
5. The interventions have been changed.
6. Phase was added.
7. The primary outcome measure has been changed.
8. The secondary outcome measures have been changed.
9. The participant inclusion criteria have been changed.
10. The target number of participants has been changed from "Planned Sample Size: 869; UK Sample Size: 652" to "Planned Sample Size: 394; UK Sample Size: 394".
11. The participant exclusion criteria have been changed.
12. The recruitment start date has been changed from 01/09/2019 to 27/01/2020.
13. The recruitment end date has been changed from 01/09/2023 to 27/01/2024.
14. Italy was deleted from the countries of recruitment.
15. Beatson West of Scotland Cancer Centre, St Bartholomew’s Hospital, University College London Hospitals, Christie Hospital, Birmingham Heartlands Hospital, The Clatterbridge Cancer Centre, The Royal Marsden Hospital and Fondazione Policlinico were removed as a trial participating centres.
16. The publication and dissemination plan has been changed.
17. The intention to publish date has been changed from 01/06/2026 to 01/06/2027.
04/11/2022: The scientific contact was updated.
07/10/2020: Cancer Research UK lay summary link added to plain English summary field.
16/06/2020: Recruitment for this study is no longer paused.
20/04/2020: Due to current public health guidance, recruitment for this study has been paused.
05/08/2019: Internal review.
08/07/2019: The funder name was changed from 'Leuka' to 'IMPACT (funded by NHS Blood & Transplant, Anthony Nolan and Leuka)'.
05/07/2019: The following changes were made to the trial record:
1. Ethics approval details added.
2. The recruitment start date was changed from 01/06/2019 to 01/09/2019.
3. The recruitment end date was changed from 01/06/2023 to 01/09/2023.
21/06/2019: Internal review.
05/04/2019: Internal review.
22/03/2019: The condition has been changed from “Specialty: Cancer, Primary sub-specialty: Haematological Oncology; Health Category: Cancer and neoplasms; Disease/Condition: Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissue” to “Acute myeloid leukaemia, myelodysplastic syndromes” following a request from the NIHR.
