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. (ALL-RIC)

NCT03821610 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: RG_17-241
• Study Type: interventional
• Target: 242
• Locations: 1 country
• Sites: 22

Brief Summary

The current national acute lymphoblastic leukaemia (ALL) trial in adults investigated whether a low (reduced) intensity chemotherapy regimen prior to transplant could improve the outcome of patients with ALL who are over 40 years of age. The results (60% 2 year survival) are very encouraging but patients who come to transplant with small amounts of 'residual' disease had less good outcomes. The goal of this trial is to see if a slightly stronger chemotherapy regimen (involving total body irradiation, (TBI)) can improve results by reducing the chance of the disease coming back (relapsing) without increasing the chance of not surviving the transplant. Up to 242 patients will be 'randomised' to the trial to receive either the established chemotherapy of fludarabine and melphalan or cyclophosphamide and TBI to compare the outcomes between the two treatment regimens. Other measures to reduce relapse will be the earlier use of donor white cell infusions and earlier stopping of immune suppressive drugs to enhance the immune effect of the transplanted cells (graft). Patients will be followed up for a minimum of 3 years. All patients on the next national ALL trial (UKALL XV) will be offered this trial but it will also be open to patients not on this study.

Conditions

Acute Lymphoblastic Leukemia

Outcome Measures

Primary Outcomes (1)

• 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 their last date known to be alive.

  The main analysis will take place once all patients have completed 2 years of follow up.

Secondary Outcomes (10)

• Overall Survival (OS)

  The main analysis will take place once all patients have completed 2 years of follow up. A subsequent analysis of long terms outcomes will be completed when all patients have completed 5 years of follow up

• Cumulative Incidence of Relapse (CIR)

  The main analysis will take place once all patients have completed 2 years of follow up. A subsequent analysis of long terms outcomes will be completed when all patients have completed 5 years of follow up

• Non-relapse mortality (NRM)

  The main analysis will take place once all patients have completed 2 years of follow up. A subsequent analysis of long terms outcomes will be completed when all patients have completed 5 years of follow up

• Incidence of chronic GvHD of any grade at 2 years

  The main analysis will take place once all patients have completed 2 years of follow up. A subsequent analysis of long terms outcomes will be completed when all patients have completed 5 years of follow up

• Occurrence and severity of VOD (Veno-occlusive disease) in the first 100 days

  The main analysis will take place once all patients have completed 2 years of follow up. A subsequent analysis of long terms outcomes will be completed when all patients have completed 5 years of follow up

Other Outcomes (2)

• Correlation of multi-lineage chimerism and relapse

  The main analysis will take place once all patients have completed 2 years of follow up. A subsequent analysis of long terms outcomes will be completed when all patients have completed 5 years of follow up

• Correlation of Minimal Residual Disease (MRD) with relapse

  The main analysis will take place once all patients have completed 2 years of follow up. A subsequent analysis of long terms outcomes will be completed when all patients have completed 5 years of follow up

Study Arms (2)

Fludarabine / Melphalan / Alemtuzumab

ACTIVE COMPARATOR

Day -7 Fludarabine 30mg/m2 od IV Day -6 Fludarabine 30mg/m2 od IV Day -5 Fludarabine 30mg/m2 od IV Day -4 Fludarabine 30mg/m2 od IV Day -3 Fludarabine 30mg/m2 od IV Day -2 Melphalan 140mg/m2 od IV, Alemtuzumab 20 mg od IV (unrelated transplants only) Day -1 Alemtuzumab 20mg od IV Day 0 Infusion of sibling or unrelated donor peripheral blood stem cells

Drug: Fludarabine; Drug: Melphalan; Drug: Alemtuzumab

Cyclophosphamide / TBI (8Gy)

EXPERIMENTAL

Day -6 Cyclophosphamide 50 mg/kg od IV , Mesna 20 mg/kg od IV, Mesna 76mg/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 (2Gy) bd Day -2 TBI (2Gy) bd, Alemtuzumab 20mg od IV (unrelated transplants only) Day -1 Alemtuzumab 20mg od IV Day 0 Infusion of sibling or unrelated donor peripheral blood stem cells or bone marrow

Drug: Alemtuzumab; Drug: Cyclophosphamide; Drug: Mesna; Radiation: Total Body Irradiation (8Gy)

Interventions

Fludarabine DRUG

IV

Fludarabine / Melphalan / Alemtuzumab

Melphalan DRUG

IV

Fludarabine / Melphalan / Alemtuzumab

Alemtuzumab DRUG

IV

Cyclophosphamide / TBI (8Gy); Fludarabine / Melphalan / Alemtuzumab

Cyclophosphamide DRUG

IV

Cyclophosphamide / TBI (8Gy)

Mesna DRUG

IV

Cyclophosphamide / TBI (8Gy)

Total Body Irradiation (8Gy) RADIATION

TBI (8Gy)

Cyclophosphamide / TBI (8Gy)

Eligibility Criteria

• Age: 40 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients between the ages of 40-70 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
• Patients with ALL in first or second CR
• Availability of a human leukocyte antigen (HLA) identical sibling or suitable matched 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
• Patients considered suitable to undergo a RIC allogeneic SCT as clinically judged by the Local Investigator including:-
• Adequate hepatic and renal function as determined by full blood count and biochemistry assessment
• 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
• Patients with abnormal cardiac and/or pulmonary function must be considered fit for allogeneic SCT including 8Gy of TBI at the time of randomisation.
• Patients with an ECOG performance status 0,1 or 2
• 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 admission for transplant conditioning therapy until 12 months after transplant (see section 8.1.2.2)
• Patients have given written informed consent
• Patients willing and able to comply with scheduled study visits and laboratory tests

You may not qualify if:

• Patients with contraindications to receiving RIC allogeneic SCT
• Female patients who are pregnant or breastfeeding. All women of childbearing potential (WOCBP) must have a negative pregnancy test before commencing treatment
• Adults of reproductive potential not willing to use appropriate, effective, contraception during the specified period
• Patients with renal or hepatic impairment as clinically judged by Local Investigator
• Patients with active infection, HIV-positive or chronic active Hep-A or -C
• 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
• Previous exposure to a high dose of radiotherapy

Sponsors & Collaborators

• University of Birmingham: lead

Study Sites (22)

Heart of England Nhs Foundation Trust

Birmingham, B95ST, United Kingdom

Location

University Hospitals Birmingham Nhs Foundation Trust

Birmingham, United Kingdom

Location

University Hospitals Bristol Nhs Foundation Trust

Bristol, BS13NU, United Kingdom

Location

Cambridge University Hospitals Nhs Foundation Trust

Cambridge, CB20QQ, United Kingdom

Location

Cardiff and Vale University Health Board

Cardiff, CF144XW, United Kingdom

Location

NHS Greater Glasgow and Clyde

Glasgow, G12 0YN, United Kingdom

Location

Leeds Teaching Hospitals Nhs Trust

Leeds, LS9 7TF, United Kingdom

Location

University Hospitals of Leicester Nhs Trust

Leicester, LE15WW, United Kingdom

Location

The Clatterbridge Cancer Centre Nhs Foundation Trust

Liverpool, CH634JY, United Kingdom

Location

Barts Health Nhs Trust

London, E11BB, United Kingdom

Location

University College London Hospitals Nhs Foundation Trust

London, NW12PG, United Kingdom

Location

Kings College Hospital

London, SE5 9RS, United Kingdom

Location

The Royal Marsden Nhs Foundation Trust

London, SW3 6JJ, United Kingdom

Location

Imperial College Healthcare Nhs Trust

London, W21NY, United Kingdom

Location

The Christie Nhs Foundation Trust

Manchester, M204BX, United Kingdom

Location

Central Manchester University Hospitals Nhs Foundation Trust

Manchester, United Kingdom

Location

The Newcastle Upon Tyne Hospitals Nhs Foundation Trust

Newcastle, United Kingdom

Location

Nottingham University Hospitals Nhs Trust

Nottingham, NG72UH, United Kingdom

Location

Oxford University Hospitals Nhs Foundation Trust

Oxford, OX3 9DU, United Kingdom

Location

Plymouth Hospitals Nhs Trust

Plymouth, PL68DH, United Kingdom

Location

Sheffield Teaching Hospitals Nhs Foundation Trust

Sheffield, S57AU, United Kingdom

Location

University Hospital Southampton Nhs Foundation Trust

Southampton, SO16 6YD, United Kingdom

Location

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

fludarabine; Melphalan; Alemtuzumab; Cyclophosphamide; Mesna; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Phosphoramides; Organophosphorus Compounds; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfhydryl Compounds; Sulfur Compounds; Sulfonic Acids; Sulfur Acids; Radiotherapy; Therapeutics; Investigative Techniques

Study Officials

• David Marks

  Bristol Haeamatology and Oncology Centre

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 9, 2019
• First Posted: January 30, 2019
• Study Start: November 22, 2018
• Primary Completion: October 31, 2025
• Study Completion (Estimated): November 22, 2027
• Last Updated: May 5, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (22)