Condition category
Cancer
Date applied
08/01/2019
Date assigned
25/01/2019
Last edited
05/04/2019
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Lay summary under review with external organisation

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

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

Publication citations

Additional files

Editorial Notes

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.