Plain English Summary
Trial website
Contact information
Type
Scientific
Primary contact
Dr Andrea Hodgkinson
ORCID ID
Contact details
CRCTU
Centre for Clinical Haematology
Queen Elizabeth Hospital
Edgbaston
Birmingham
B15 2TH
United Kingdom
-
a.hodgkinson@bham.ac.uk
Type
Public
Additional contact
Mr Nicholas Martin
ORCID ID
Contact details
CRCTU
Centre for Clinical Haematology
Queen Elizabeth Hospital
Edgbaston
Birmingham
B15 2TH
United Kingdom
+44 (0)121 371 7856
ALL-RIC@trials.bham.ac.uk
Additional identifiers
EudraCT number
2017-004800-23
ClinicalTrials.gov number
NCT03821610
Protocol/serial number
38207; RG_17_241
Study information
Scientific title
A comparison of reduced dose total body irradiation (TBI) and cyclophosphamide with fludarabine and melphalan reduced intensity conditioning in adults with acute lymphoblastic leukaemia (ALL) in complete remission
Acronym
ALL-RIC
Study hypothesis
The UKALL XIV trial has prospectively studied reduced intensity conditioning (RIC) transplants in adults with acute lymphoblastic leukaemia (ALL) in first remission over 40 years of age. Given this group had 15-20% survival in the previous UKALL XII trial, the 56% 2 year disease-free-survival (DFS) is encouraging. However, relapse at 2 years is high at 27%, especially in patients who come to transplant minimal residual disease (MRD) positive. Previous studies suggested that total body irradiation (TBI) conditioning in patients who received full intensity or RIC transplants reduced treatment failure (OR 1.4). The trialists propose to compare the two conditioning regimens and postulate that total body irradiation (TBI) 8Gy and cyclophosphamide 100mg/kg will be well tolerated and will reduce relapse. Experience from the German group with 8Gy TBI and in the SCOT trial suggests that this regimen is well tolerated with minimal extramedullary toxicity and low transplant related mortality (TRM).
Ethics approval
East Midlands - Leicester Central Research Ethics Committee, The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS, Tel: +44 (0)207 104 8098; Email: nrescommittee.eastmidlands-leicestercentral@nhs.net, 12/06/2018, ref: 18/EM/0112
Study design
Randomised; Interventional; Design type: Treatment, Drug, Radiotherapy
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 lymphoblastic leukaemia
Intervention
This is a two-arm phase II, multicentre, randomised clinical trial comparing the outcome of patients transplanted using a TBI and cyclophosphamide allograft with patients transplanted with a FMA conditioning regimen. Patients with ALL who fulfil the eligibility criteria will be invited to participate in the trial across UK centres performing allogeneic SCT.
Patients will be randomised to treatment based on a minimisation algorithm prepared at the Cancer Research UK Clinical Trials Unit (CRCTU). Minimisation will be based upon age (>55; <55 years) and by donor type (sibling; unrelated).
Active Comparator: Fludarabine / Melphalan / Alemtuzumab
Day -7: Fludarabine 30 mg/m2 od IV
Day -6: Fludarabine 30 mg/m2 od IV
Day -5: Fludarabine 30 mg/m2 od IV
Day -4: Fludarabine 30 mg/m2 od IV
Day -3: Fludarabine 30 mg/m2 od IV
Day -2: Melphalan 140 mg/m2 od IV, Alemtuzumab 30 mg od IV (unrelated transplants only)
Day -1: Alemtuzumab 30 mg od IV
Day 0: Infusion of sibling or unrelated donor peripheral blood stem cells
Experimental: Cyclophosphamide / TBI (8 Gy)
Day -6: Cyclophosphamide 50 mg/kg od IV , Mesna 20 mg/kg od IV, Mesna 76 mg/kg od IV
Day -5: Cyclophosphamide 50 mg/kg od IV, Mesna 20 mg/kg od IV, Mesna 76 mg/kg od IV
Day -4: Rest
Day -3: TBI (2 Gy) bd
Day -2: TBI (2 Gy) bd, Alemtuzumab 30 mg od IV (unrelated transplants only)
Day -1: Alemtuzumab 30 mg od IV
Day 0: Infusion of sibling or unrelated donor peripheral blood stem cells or bone marrow
Patients will be followed-up for a minimum of 5 years from the date of randomisation.
Intervention type
Drug
Phase
Phase II
Drug names
Fludarabine, melphalan, alemtuzumab, cyclophosphamide, mesna
Primary outcome measure
Disease Free Survival (DFS) defined as time from randomisation to the first of relapse or death from any cause. Patients who are still alive and progression free at the end of the trial will be censored at the date they were last known to be alive. Bone marrow assessments carried out to assess disease status at baseline, Day 100, Month 6/9/12/15/18/21/24/30/36
Secondary outcome measures
1. Overall Survival defined as time from randomisation to date of death from any cause. Patients who are alive at the end of the trial will be censored at their date last known to be alive. Information will be captured on a Death Form Case Report Form (CRF).
2. Cumulative Incidence of Relapse (CIR) defined as time from randomisation to the date of relapse. Patients who die without 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 as their date last seen
3. Non Relapse Mortality (NRM) defined as time from randomisation to death from any cause that occurred without relapse. Patients who relapse will be treated as a competing risk and patients who are still alive and relapse free at the end of the trial will be censored at their date last known to be alive. Incidence of Grade 2-4 acute GvHD within 100 days of transplant. GvHD should be assessed continuously throughout the trial according to Glucksberg Criteria (see Appendix 4 of protocol)
4. Incidence of chronic GvHD of any grade at 2 years. See above.
5. Occurrence and severity of VOD in the first 100 days, captured on a specific Veno-Occlusive Disease CRF (which is based on the new EBMT criteria for SOS/VOD diagnosis in adults). All post-transplant events of VOD should be reported as a SAE irrespective of how long after IMP has been administered.
6. Duration of hospitalisation recorded on Hospitalisation Form CRF between start of conditioning regimen and 1 year post transplantation
7. Quality of life assessed using SF36 and FACT-BMT at baseline, 3 months, 12 months and years 2, 3, 4 and 5
8. Full donor chimerism recorded at day 100 follow up
9. Occurrence and severity of TBI-related symptomatic pulmonary toxicity in the first 12 months. Assessed using: Forced Expiratory Volume (FEV) 1 (%), Forced Vital Capacity (FVC) (%), % of predicted Peak Expiratory Flow Rate (PEFR), corrected for HL (%), Single Breath diffusing capacity of the lungs for carbon monoxide (DLCO) (%)
Exploratory outcome measures:
1. Correlation of multi-lineage chimerism and relapse
2. Correlation of MRD with relapse. There is a specific MRD CRF
Cumulative incidence of relapse will be assessed by both MRD and multi-lineage chimerism using cumulative incidence curves and multivariable cox models. Analysis will be conducted when patients have been followed up for 2 years
Overall trial start date
07/07/2017
Overall trial end date
22/11/2027
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
Patients with morphologically documented ALL who meet the following criteria;
1. Patients between the ages of 40-65 years. NB: Patients under the age of 40 who are considered unsuitable for a myeloablative transplant may enrol onto the trial following discussion with the CI via the Trials Office
2. Patients with ALL in first CR
3. Availability of a human leukocyte antigen (HLA) identical sibling or suitable matched unrelated donor (suitable matched defined as no greater than a single allele mismatch at HLA A, B, C or DRβ1). A single allele mismatch is permitted if there are adverse cytogenetics or MRD positivity at any timepoint
4. Patients considered suitable to undergo a RIC allogeneic 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). Patients with bone marrow suppression following therapy may enter the trial
4.3. Patients with abnormal cardiac and/or pulmonary function must be considered fit for allogeneic SCT including 8Gy of TBI at the time of randomisation.
5. Patients with an ECOG performance status 0,1 or 2
6. Female 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 admission for transplant conditioning therapy until 12 months after transplant
7. Patients have given written informed consent
8. Patients willing and able to comply with scheduled study visits and laboratory tests
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Planned Sample Size: 242; UK Sample Size: 242
Participant exclusion criteria
1. Patients with contraindications to receiving RIC allogeneic SCT
2. Female patients who are pregnant or breastfeeding. All women of childbearing potential (WOCBP) 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 Local Investigator
5. Patients with active infection, HIV-positive or chronic active Hep-A or -C
6. Patients with concurrent active malignancy. Patients with a previous history of malignancy can be included if that malignancy is considered to be at a low risk of recurrence
Recruitment start date
22/11/2018
Recruitment end date
22/11/2022
Locations
Countries of recruitment
United Kingdom
Trial participating centre
NHS Greater Glasgow and Clyde
Department of Haematology
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom
Trial participating centre
King's College Hospital
Denmark Hill
Brixton
London
SE5 9RS
United Kingdom
Trial participating centre
Leeds Teaching Hospitals NHS Trust
St. James's University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom
Trial participating centre
Central Manchester University Hospitals NHS Foundation Trust
Trust Headquarters
Cobbett House
Oxford Road
Manchester
M13 9WL
United Kingdom
Trial participating centre
The Newcastle Upon Tyne Hospitals NHS Foundation Trust
Freeman Hospital
Freeman Road
High Heaton
Newcastle-Upon-Tyne
NE7 7DN
United Kingdom
Trial participating centre
Oxford University Hospitals NHS Foundation Trust
John Radcliffe Hospital
Headley Way
Headington
Oxford
OX3 9DU
United Kingdom
Trial participating centre
University Hospitals Birmingham NHS Foundation Trust
Trust HQ, PO Box 9551
Queen Elizabeth Medical Centre
Edgbaston
Birmingham
B15 2TH
United Kingdom
Trial participating centre
Barts Health NHS Trust
The Royal London Hospital
Whitechapel
London
E1 1BB
United Kingdom
Trial participating centre
University Hospitals Bristol NHS Foundation Trust
Marlborough Street
Bristol
BS1 3NU
United Kingdom
Trial participating centre
University College London Hospitals NHS Foundation Trust
250 Euston Road
London
NW1 2PG
United Kingdom
Trial participating centre
Cambridge University Hospitals NHS Foundation Trust
Addenbrookes Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Trial participating centre
Cardiff and Vale University Health Board
University Hospital of Wales
Heath Park
Cardiff
CF14 4XW
United Kingdom
Trial participating centre
The Christie NHS Foundation Trust
550 Wilmslow Road
Withington
Manchester
M20 4BX
United Kingdom
Trial participating centre
Imperial College Healthcare NHS Trust
St Marys Hospital
Praed Street
London
W2 1NY
United Kingdom
Trial participating centre
Heart of England NHS Foundation Trust
Birmingham Heartlands Hospital
Bordesley Green East
Birmingham
B9 5ST
United Kingdom
Trial participating centre
University Hospitals of Leicester NHS Trust
Leicester Royal Infirmary
Infirmary Square
Leicester
LE1 5WW
United Kingdom
Trial participating centre
The Clatterbridge Cancer Centre NHS Foundation Trust
Clatterbridge Road
Bebington
Liverpool
CH63 4JY
United Kingdom
Trial participating centre
Nottingham University Hospitals NHS Trust
Trust Headquarters
Queens Medical Centre
Derby Road
Nottingham
NG7 2UH
United Kingdom
Trial participating centre
Plymouth Hospitals NHS Trust
Derriford Hospital
Derriford Road
Plymouth
PL6 8DH
United Kingdom
Trial participating centre
The Royal Marsden NHS Foundation Trust
Fulham Road
London
SW3 6JJ
United Kingdom
Trial participating centre
Sheffield Teaching Hospitals NHS Foundation Trust
Northern General Hospital
Herries Road
Sheffield
S5 7AU
United Kingdom
Trial participating centre
University Hospital Southampton NHS Foundation Trust
Mailpoint 18
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom
Sponsor information
Organisation
University of Birmingham
Sponsor details
CRCTU
Institute of Cancer and Genomic Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
+44 (0)121 371 7856
ALL-RIC@trials.bham.ac.uk
Sponsor type
Hospital/treatment centre
Website
Funders
Funder type
Charity
Funder name
IMPACT Partnership - Leuka, Anthony Nolan, BSBMT
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
1. Protocol is available on request from ALL-RIC@trials.bham.ac.uk
2. Abstract submission to ASH 2028
3. Full publication end of 2028/2029
IPD sharing statement
Trial data will be made available through the EU portal at the end of the trial.
Intention to publish date
30/09/2028
Participant level data
Stored in repository
Basic results (scientific)
Publication list