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)

  • STATUS
    Recruiting
  • End date
    Nov 22, 2027
  • participants needed
    242
  • sponsor
    University of Birmingham
Updated on 24 January 2021
remission
total body irradiation
fludarabine
cyclophosphamide
hla-a
melphalan
myeloablative conditioning
transplant conditioning
alemtuzumab
blood cell count

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.

Description

TRIAL SYNOPSIS

Trial Design This is a 2 arm, phase II, multicentre, randomised clinical trial in adult patients with ALL in complete remission (CR) undergoing allogeneic stem cell transplantation (SCT) comparing the novel conditioning regimen of TBI and cyclophosphamide with the standard condition of Fludarabine/Melphalan/Alemtuzumab (FMA).

Patient will be stratified at randomisation by the donor type (sibling; suitable matched), CR status (CR1; CR2) and by age (above; below 55 years of age). Patients eligible for entry into the trial will be randomised on a 1:1 basis to receive either the experimental treatment arm or the control arm.

Objectives Primary Objectives To compare the disease free survival (DFS) at two years of patients with ALL after a TBI and cyclophosphamide allograft with that of patients transplanted using the FMA conditioning regimen.

Secondary Objectives To compare overall survival (OS), cumulative incidence of disease relapse (CIR), non-relapse mortality (NRM), incidence of grade 2-4 acute graft-versus-host-disease (GvHD), incidence of chronic GvHD of any grade, occurrence and severity of veno-occlusive disease (VOD), duration of hospitalisation in the first year, quality of life (QoL), full donor chimerism at day 100 and TBI related symptomatic pulmonary toxicity between the control and experimental arm following allogenic SCT.

Exploratory Objectives To measure multi-lineage chimerism and molecular minimal residual disease (MRD) at 3 monthly intervals and the ability of planned donor lymphocyte infusion (DLI) to 'correct' mixed chimerism and reverse molecular relapse/persistence and reduce the incidence of frank haematologic relapse.

To ascertain if either of the conditioning arms is more effective in controlling disease in patients who are MRD positive before transplant.

Patient Population This trial will recruit patients with ALL in CR as defined by the WHO classification (Appendix 1). Patients enrolled onto the UKALL XIV registration study and the planned national UKALL XV study who are eligible for transplant will also be able to enrol onto ALL-RIC provided they meet the entry criteria.

Sample Size A minimum of 247 patients will be randomised 1:1 between the control and experimental treatment arms.

Trial Duration Patients will be recruited over 48 months across IMPACT centres. Patients will be followed up for a minimum of 5 years.

Details
Condition childhood ALL, Lymphocytic Leukemia, Acute, acute lymphoblastic leukemia, leukemia, acute lymphoblastic, acute lymphoid leukaemia, acute lymphocytic leukemia, acute lymphoblastic leukemia (all)
Treatment cyclophosphamide, melphalan, Fludarabine, MESNA, alemtuzumab, Total Body Irradiation (8Gy)
Clinical Study IdentifierNCT03821610
SponsorUniversity of Birmingham
Last Modified on24 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

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 DR1). 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](telnet://8.1.2.2))
Patients have given written informed consent
Patients willing and able to comply with scheduled study visits and laboratory tests

Exclusion Criteria

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
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