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)

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.

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 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

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