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
ClinicalTrials.gov (NCT)	NCT03821610
Clinical Trials Information System (CTIS)	2017-004800-23
Protocol serial number	38207; RG_17_241
Sponsor	University of Birmingham
Funder	IMPACT Partnership - Leuka, Anthony Nolan, BSBMT

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

Available at: https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-comparing-treatments-for-acute-lymphoblastic-leukaemia-all-ric

Contact information

Dr Andrea Hodgkinson
Scientific

CRCTU, Centre for Clinical Haematology
Queen Elizabeth Hospital
Edgbaston
Birmingham
B15 2TH
United Kingdom

Email	a.hodgkinson@bham.ac.uk

Mr Nicholas Martin
Public

CRCTU, Centre for Clinical Haematology
Queen Elizabeth Hospital, Edgbaston
Birmingham
B15 2TH
United Kingdom

Phone	+44 (0)121 371 7856
Email	ALL-RIC@trials.bham.ac.uk

Study information

Primary study design	Interventional
Study design	Randomised; Interventional; Design type: Treatment, Drug, Radiotherapy
Secondary study design	Randomised controlled trial
Study type	Participant 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
Phase	Phase II
Drug / device / biological / vaccine name(s)	Fludarabine, melphalan, alemtuzumab, cyclophosphamide, mesna
Primary outcome measure(s)	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
Key secondary outcome measure(s)	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
Completion date	22/11/2027

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	All
Target sample size at registration	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

United Kingdom
England
Scotland
Wales

Study participating centres

NHS Greater Glasgow and Clyde

Department of Haematology
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

King's College Hospital

Denmark Hill
Brixton
London
SE5 9RS
United Kingdom

Leeds Teaching Hospitals NHS Trust

St. James's University Hospital
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

The Newcastle Upon Tyne Hospitals NHS Foundation Trust

Freeman Hospital
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

University Hospitals Birmingham NHS Foundation Trust

Trust HQ, PO Box 9551
Queen Elizabeth Medical Centre
Edgbaston
Birmingham
B15 2TH
United Kingdom

Barts Health NHS Trust

The Royal London Hospital
Whitechapel
London
E1 1BB
United Kingdom

University Hospitals Bristol NHS Foundation Trust

Marlborough Street
Bristol
BS1 3NU
United Kingdom

University College London Hospitals NHS Foundation Trust

250 Euston Road
London
NW1 2PG
United Kingdom

Cambridge University Hospitals NHS Foundation Trust

Addenbrookes Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom

Cardiff and Vale University Health Board

University Hospital of Wales
Heath Park
Cardiff
CF14 4XW
United Kingdom

The Christie NHS Foundation Trust

550 Wilmslow Road
Withington
Manchester
M20 4BX
United Kingdom

Imperial College Healthcare NHS Trust

St Marys Hospital
Praed Street
London
W2 1NY
United Kingdom

Heart of England NHS Foundation Trust

Birmingham Heartlands Hospital
Bordesley Green East
Birmingham
B9 5ST
United Kingdom

University Hospitals of Leicester NHS Trust

Leicester Royal Infirmary
Infirmary Square
Leicester
LE1 5WW
United Kingdom

The Clatterbridge Cancer Centre NHS Foundation Trust

Clatterbridge Road
Bebington
Liverpool
CH63 4JY
United Kingdom

Nottingham University Hospitals NHS Trust

Trust Headquarters
Queens Medical Centre
Derby Road
Nottingham
NG7 2UH
United Kingdom

Plymouth Hospitals NHS Trust

Derriford Hospital
Derriford Road
Plymouth
PL6 8DH
United Kingdom

The Royal Marsden NHS Foundation Trust

Fulham Road
London
SW3 6JJ
United Kingdom

Sheffield Teaching Hospitals NHS Foundation Trust

Northern General Hospital
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

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Stored in repository
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
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

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.