Condition category
Cancer
Date applied
18/03/2019
Date assigned
20/03/2019
Last edited
05/04/2019
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Plain English summary under review with external organisation

Trial website

Contact information

Type

Scientific

Primary contact

Dr Eszter Nagy

ORCID ID

Contact details

Haematology Team – IMPACT
Room 15
Centre for Clinical Haematology
Queen Elizabeth Hospital
Edgbaston
Birmingham
B15 2TH
United Kingdom
+44 (0)121 371 7858
e.nagy@bham.ac.uk

Additional identifiers

EudraCT number

2017-004801-42

ClinicalTrials.gov number

Nil known

Protocol/serial number

41409

Study information

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

Acronym

COSI

Study hypothesis

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

Approval pending from North West - Liverpool Central Research Ethics Committee, 3rd Floor, Barlow House, 4 Minshull Street, Manchester, M1 3DZ, Tel: +44 (0)207 104 8196, Email: nrescommittee.northwest-liverpoolcentral@nhs.net, ref: 19/NW/0135

Study design

Randomised; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

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

Phase

Not Applicable

Drug names

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

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 trial start date

07/07/2017

Overall trial end date

01/06/2025

Reason abandoned (if study stopped)

Eligibility

Participant 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)
1.1.2. Patients in 2nd complete remission (CR2)
1.1.3. Secondary AML (defined as previous history of MDS, antecedent haematological disease or chemotherapy
exposure) in CR1 or 2
1.2. MDS:
1.2.1 Patients with 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 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)
1.1.2. Patients in 2nd complete remission (CR2)
1.1.3. Secondary AML (defined as previous history of MDS, antecedent haematological disease or chemotherapy exposure) in CR1 or 2
1.1.4. Must have received at least two courses of prior intensive chemotherapy prior to transplant unless there are exceptional circumstances
1.2. MDS:
1.2.1 Patients with 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 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 with one of the following disease characteristics:
1.1. AML
1.1.1. Patients in 1st complete remission (CR1)
1.1.2. Patients in 2nd complete remission (CR2)
1.1.3. Secondary AML (defined as previous history of MDS, antecedent haematological disease or chemotherapy exposure) in CR1 or 2
1.1.4. Must have received at least two courses of prior intensive chemotherapy prior to transplant unless there are exceptional circumstances
1.2. MDS
1.2.1. Patients with 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 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 schedule

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 869; UK Sample Size: 652

Participant exclusion criteria

Exclusion criteria for Randomisation 1 (R1):
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 concurrent active malignancy. Patients with a previous history of malignancy can be included if that malignancy is considered to be at low risk of recurrence
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

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 concurrent active malignancy. Patients with a previous history of malignancy can be included if that malignancy is considered to be at low risk of recurrence

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 concurrent active malignancy. Patients with a previous history of malignancy can be included if that malignancy is considered to be at low risk of recurrence

Recruitment start date

01/06/2019

Recruitment end date

01/06/2023

Locations

Countries of recruitment

Italy, United Kingdom

Trial participating centre

Beatson West of Scotland Cancer Centre
Glasgow
G12 0YN
United Kingdom

Trial participating centre

King's College Hospital
London
SE5 9RS
United Kingdom

Trial participating centre

St James's University Hospital
Leeds
LS9 7TF
United Kingdom

Trial participating centre

Manchester Royal Infirmary
Manchester
M13 9WL
United Kingdom

Trial participating centre

Freeman Hospital
Newcastle-Upon-Tyne
NE7 7DN
United Kingdom

Trial participating centre

Churchill Hospital
Oxford
OX3 7LE
United Kingdom

Trial participating centre

Queen Elizabeth Hospital
Birmingham
B15 2TH
United Kingdom

Trial participating centre

St Bartholomew’s Hospital
London
EC1A 7BE
United Kingdom

Trial participating centre

Bristol Haematology and Oncology Centre
Bristol
BS2 8ED
United Kingdom

Trial participating centre

University College London Hospitals
London
NW1 2BU
United Kingdom

Trial participating centre

Addenbrookes Hospital
Cambridge
CB2 0QQ
United Kingdom

Trial participating centre

University Hospital of Wales
Cardiff
CF14 4XW
United Kingdom

Trial participating centre

Christie Hospital
Manchester
M20 4BX
United Kingdom

Trial participating centre

Hammersmith Hospital
London
W12 0HS
United Kingdom

Trial participating centre

Birmingham Heartlands Hospital
Birmingham
B9 5SS
United Kingdom

Trial participating centre

Leicester Royal Infirmary
Leicester
LE1 5WW
United Kingdom

Trial participating centre

The Clatterbridge Cancer Centre
Liverpool
CH63 4JY
United Kingdom

Trial participating centre

Nottingham City Hospital
Nottingham
NG5 1PB
United Kingdom

Trial participating centre

Derriford Hospital
Plymouth
PL6 8DH
United Kingdom

Trial participating centre

The Royal Marsden Hospital
London
SW3 6JJ
United Kingdom

Trial participating centre

Royal Hallamshire Hospital
Sheffield
S5 7AU
United Kingdom

Trial participating centre

Southampton General Hospital
Southampton
SO16 6YD
United Kingdom

Trial participating centre

Royal Stoke University Hospital
Stoke-on-Trent
ST4 6QG
United Kingdom

Trial participating centre

ASST Papa Giovanni XXIII
BERGAMO
24127
Italy

Trial participating centre

Fondazione Policlinico
Universitario A. Gemelli
Rome
00168
Italy

Sponsor information

Organisation

University of Birmingham

Sponsor details

Research Support Group
Aston Webb Building
Edgbaston
Birmingham
B15 2TT
United Kingdom
+44 (0)121 371 7858
cosi@trials.bham.ac.uk

Sponsor type

University/education

Website

Funders

Funder type

Industry

Funder name

Leuka

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

Trusts, charities, foundations (both publically funded and privately funded)

Location

United Kingdom

Funder name

Jazz Pharmaceuticals

Alternative name(s)

Jazz Pharmaceuticals plc

Funding Body Type

private sector organisation

Funding Body Subtype

For-profit companies (industry)

Location

Ireland

Funder name

ADIENNE SA

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer-reviewed journal in 2026.

IPD sharing statement
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

01/06/2026

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

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.