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)

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Brief 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. (ALL-RIC)

Official 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. (ALL-RIC)

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.
    

Detailed 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; unrelated) 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 242 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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Disease Free Survival (DFS)

Secondary Outcome

 Overall Survival (OS)

Condition

Acute Lymphoblastic Leukemia

Intervention

Fludarabine

Study Arms / Comparison Groups

 Fludarabine / Melphalan / Alemtuzumab
Description:  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 30 mg od IV (unrelated transplants only) Day -1 Alemtuzumab 30mg od IV Day 0 Infusion of sibling or unrelated donor peripheral blood stem cells

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

242

Start Date

November 22, 2018

Completion Date

November 22, 2027

Primary Completion Date

November 22, 2024

Eligibility Criteria

        Inclusion Criteria:

          -  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

          -  Patients with ALL in first CR

          -  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

          -  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
      

Gender

All

Ages

40 Years - 65 Years

Accepts Healthy Volunteers

No

Contacts

David Marks, +441213717856, [email protected]

Location Countries

United Kingdom

Location Countries

United Kingdom

Administrative Informations


NCT ID

NCT03821610

Organization ID

RG_17-241


Responsible Party

Sponsor

Study Sponsor

University of Birmingham


Study Sponsor

David Marks, Study Chair, Bristol Haeamatology and Oncology Centre


Verification Date

January 2019