A comparison of two low-intensity transplant regimens for the treatment of adults with acute lymphoblastic leukaemia (ALL) over the age of 40 years (ALL-RIC trial)
| ISRCTN | ISRCTN99927695 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN99927695 |
| EudraCT/CTIS number | 2017-004800-23 |
| ClinicalTrials.gov number | NCT03821610 |
| Secondary identifying numbers | 38207; RG_17_241 |
- Submission date
- 08/01/2019
- Registration date
- 25/01/2019
- Last edited
- 06/06/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- 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 Andrea Hodgkinson
Scientific
Scientific
CRCTU, Centre for Clinical Haematology
Queen Elizabeth Hospital
Edgbaston
Birmingham
B15 2TH
United Kingdom
| a.hodgkinson@bham.ac.uk |
Mr Nicholas Martin
Public
Public
CRCTU, Centre for Clinical Haematology
Queen Elizabeth Hospital, Edgbaston
Birmingham
B15 2TH
United Kingdom
| Phone | +44 (0)121 371 7856 |
|---|---|
| ALL-RIC@trials.bham.ac.uk |
Study information
| Study design | Randomised; Interventional; Design type: Treatment, Drug, Radiotherapy |
|---|---|
| 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 | 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 |
| Study acronym | ALL-RIC |
| Study objectives | 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(s) | 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 |
| Health condition(s) or problem(s) studied | 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 |
| Pharmaceutical study type(s) | |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | 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 study start date | 07/07/2017 |
| Completion date | 22/11/2027 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Both |
| Target number of participants | Planned Sample Size: 242; UK Sample Size: 242 |
| Total final enrolment | 102 |
| Key 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 |
| Key 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 |
| Date of first enrolment | 22/11/2018 |
| Date of final enrolment | 22/11/2022 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
NHS Greater Glasgow and Clyde
Department of Haematology
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom
King's College Hospital
Denmark Hill
Brixton
London
SE5 9RS
United Kingdom
Brixton
London
SE5 9RS
United Kingdom
Leeds Teaching Hospitals NHS Trust
St. James's University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom
Beckett Street
Leeds
LS9 7TF
United Kingdom
Central Manchester University Hospitals NHS Foundation Trust
Trust Headquarters
Cobbett House
Oxford Road
Manchester
M13 9WL
United Kingdom
Cobbett House
Oxford Road
Manchester
M13 9WL
United Kingdom
The Newcastle Upon Tyne Hospitals NHS Foundation Trust
Freeman Hospital
Freeman Road
High Heaton
Newcastle-Upon-Tyne
NE7 7DN
United Kingdom
Freeman Road
High Heaton
Newcastle-Upon-Tyne
NE7 7DN
United Kingdom
Oxford University Hospitals NHS Foundation Trust
John Radcliffe Hospital
Headley Way
Headington
Oxford
OX3 9DU
United Kingdom
Headley Way
Headington
Oxford
OX3 9DU
United Kingdom
University Hospitals Birmingham NHS Foundation Trust
Trust HQ, PO Box 9551
Queen Elizabeth Medical Centre
Edgbaston
Birmingham
B15 2TH
United Kingdom
Queen Elizabeth Medical Centre
Edgbaston
Birmingham
B15 2TH
United Kingdom
Barts Health NHS Trust
The Royal London Hospital
Whitechapel
London
E1 1BB
United Kingdom
Whitechapel
London
E1 1BB
United Kingdom
University Hospitals Bristol NHS Foundation Trust
Marlborough Street
Bristol
BS1 3NU
United Kingdom
Bristol
BS1 3NU
United Kingdom
University College London Hospitals NHS Foundation Trust
250 Euston Road
London
NW1 2PG
United Kingdom
London
NW1 2PG
United Kingdom
Cambridge University Hospitals NHS Foundation Trust
Addenbrookes Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Cardiff and Vale University Health Board
University Hospital of Wales
Heath Park
Cardiff
CF14 4XW
United Kingdom
Heath Park
Cardiff
CF14 4XW
United Kingdom
The Christie NHS Foundation Trust
550 Wilmslow Road
Withington
Manchester
M20 4BX
United Kingdom
Withington
Manchester
M20 4BX
United Kingdom
Imperial College Healthcare NHS Trust
St Marys Hospital
Praed Street
London
W2 1NY
United Kingdom
Praed Street
London
W2 1NY
United Kingdom
Heart of England NHS Foundation Trust
Birmingham Heartlands Hospital
Bordesley Green East
Birmingham
B9 5ST
United Kingdom
Bordesley Green East
Birmingham
B9 5ST
United Kingdom
University Hospitals of Leicester NHS Trust
Leicester Royal Infirmary
Infirmary Square
Leicester
LE1 5WW
United Kingdom
Infirmary Square
Leicester
LE1 5WW
United Kingdom
The Clatterbridge Cancer Centre NHS Foundation Trust
Clatterbridge Road
Bebington
Liverpool
CH63 4JY
United Kingdom
Bebington
Liverpool
CH63 4JY
United Kingdom
Nottingham University Hospitals NHS Trust
Trust Headquarters
Queens Medical Centre
Derby Road
Nottingham
NG7 2UH
United Kingdom
Queens Medical Centre
Derby Road
Nottingham
NG7 2UH
United Kingdom
Plymouth Hospitals NHS Trust
Derriford Hospital
Derriford Road
Plymouth
PL6 8DH
United Kingdom
Derriford Road
Plymouth
PL6 8DH
United Kingdom
The Royal Marsden NHS Foundation Trust
Fulham Road
London
SW3 6JJ
United Kingdom
London
SW3 6JJ
United Kingdom
Sheffield Teaching Hospitals NHS Foundation Trust
Northern General Hospital
Herries Road
Sheffield
S5 7AU
United Kingdom
Herries Road
Sheffield
S5 7AU
United Kingdom
University Hospital Southampton NHS Foundation Trust
Mailpoint 18
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom
Sponsor information
University of Birmingham
University/education
University/education
CRCTU, Institute of Cancer and Genomic Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
| Phone | +44 (0)121 371 7856 |
|---|---|
| ALL-RIC@trials.bham.ac.uk | |
"ROR" |
https://ror.org/03angcq70 |
Funders
Funder type
Charity
IMPACT Partnership - Leuka, Anthony Nolan, BSBMT
No information available
Results and Publications
| Intention to publish date | 30/09/2028 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Stored in repository |
| 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 plan | Trial data will be made available through the EU portal at the end of the trial. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | 01/06/2023 | 02/06/2023 | Yes | No | |
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
06/06/2024: A study contact confirmed that the record information was up to date.
02/06/2023: Publication reference added.
15/12/2022: Total final enrolment added.
20/09/2021: Internal review.
12/05/2020: Recruitment to this study is no longer paused.
27/04/2020: Due to current public health guidance, recruitment for this study has been paused as of 24/03/2020.
26/06/2019: Cancer Research UK lay summary link added to plain English summary field.
21/06/2019: Internal review.
24/05/2019: ClinicalTrials.gov number added.
05/04/2019: Internal review.
25/03/2019: 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 lymphoblastic leukaemia" following a request from the NIHR.
05/03/2019: Internal review.
