<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03821610</url>
  </required_header>
  <id_info>
    <org_study_id>RG_17-241</org_study_id>
    <nct_id>NCT03821610</nct_id>
  </id_info>
  <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)</brief_title>
  <acronym>ALL-RIC</acronym>
  <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)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Birmingham</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Birmingham</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The current national acute lymphoblastic leukaemia (ALL) trial in adults investigated whether&#xD;
      a low (reduced) intensity chemotherapy regimen prior to transplant could improve the outcome&#xD;
      of patients with ALL who are over 40 years of age. The results (60% 2 year survival) are very&#xD;
      encouraging but patients who come to transplant with small amounts of 'residual' disease had&#xD;
      less good outcomes. The goal of this trial is to see if a slightly stronger chemotherapy&#xD;
      regimen (involving total body irradiation, (TBI)) can improve results by reducing the chance&#xD;
      of the disease coming back (relapsing) without increasing the chance of not surviving the&#xD;
      transplant. Up to 242 patients will be 'randomised' to the trial to receive either the&#xD;
      established chemotherapy of fludarabine and melphalan or cyclophosphamide and TBI to compare&#xD;
      the outcomes between the two treatment regimens. Other measures to reduce relapse will be the&#xD;
      earlier use of donor white cell infusions and earlier stopping of immune suppressive drugs to&#xD;
      enhance the immune effect of the transplanted cells (graft). Patients will be followed up for&#xD;
      a minimum of 3 years. All patients on the next national ALL trial (UKALL XV) will be offered&#xD;
      this trial but it will also be open to patients not on this study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      TRIAL SYNOPSIS&#xD;
&#xD;
      Trial Design This is a 2 arm, phase II, multicentre, randomised clinical trial in adult&#xD;
      patients with ALL in complete remission (CR) undergoing allogeneic stem cell transplantation&#xD;
      (SCT) comparing the novel conditioning regimen of TBI and cyclophosphamide with the standard&#xD;
      condition of Fludarabine/Melphalan/Alemtuzumab (FMA).&#xD;
&#xD;
      Patient will be stratified at randomisation by the donor type (sibling; suitable matched), CR&#xD;
      status (CR1; CR2) and by age (above; below 55 years of age). Patients eligible for entry into&#xD;
      the trial will be randomised on a 1:1 basis to receive either the experimental treatment arm&#xD;
      or the control arm.&#xD;
&#xD;
      Objectives Primary Objectives To compare the disease free survival (DFS) at two years of&#xD;
      patients with ALL after a TBI and cyclophosphamide allograft with that of patients&#xD;
      transplanted using the FMA conditioning regimen.&#xD;
&#xD;
      Secondary Objectives To compare overall survival (OS), cumulative incidence of disease&#xD;
      relapse (CIR), non-relapse mortality (NRM), incidence of grade 2-4 acute&#xD;
      graft-versus-host-disease (GvHD), incidence of chronic GvHD of any grade, occurrence and&#xD;
      severity of veno-occlusive disease (VOD), duration of hospitalisation in the first year,&#xD;
      quality of life (QoL), full donor chimerism at day 100 and TBI related symptomatic pulmonary&#xD;
      toxicity between the control and experimental arm following allogenic SCT.&#xD;
&#xD;
      Exploratory Objectives To measure multi-lineage chimerism and molecular minimal residual&#xD;
      disease (MRD) at 3 monthly intervals and the ability of planned donor lymphocyte infusion&#xD;
      (DLI) to 'correct' mixed chimerism and reverse molecular relapse/persistence and reduce the&#xD;
      incidence of frank haematologic relapse.&#xD;
&#xD;
      To ascertain if either of the conditioning arms is more effective in controlling disease in&#xD;
      patients who are MRD positive before transplant.&#xD;
&#xD;
      Patient Population This trial will recruit patients with ALL in CR as defined by the WHO&#xD;
      classification (Appendix 1). Patients enrolled onto the UKALL XIV registration study and the&#xD;
      planned national UKALL XV study who are eligible for transplant will also be able to enrol&#xD;
      onto ALL-RIC provided they meet the entry criteria.&#xD;
&#xD;
      Sample Size A minimum of 247 patients will be randomised 1:1 between the control and&#xD;
      experimental treatment arms.&#xD;
&#xD;
      Trial Duration Patients will be recruited over 48 months across IMPACT centres. Patients will&#xD;
      be followed up for a minimum of 5 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 22, 2018</start_date>
  <completion_date type="Anticipated">November 22, 2027</completion_date>
  <primary_completion_date type="Anticipated">November 22, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Disease Free Survival (DFS)</measure>
    <time_frame>The main analysis will take place once all patients have completed 2 years of follow up.</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>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</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative Incidence of Relapse (CIR)</measure>
    <time_frame>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</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Non-relapse mortality (NRM)</measure>
    <time_frame>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</time_frame>
    <description>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 aliveIncidence of Grade 2-4 acute GvHD within 100 days of transplant</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of chronic GvHD of any grade at 2 years</measure>
    <time_frame>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</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Occurrence and severity of VOD (Veno-occlusive disease) in the first 100 days</measure>
    <time_frame>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</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of hospitalisation</measure>
    <time_frame>The outcome will be conducted when all patients have completed 1 year of follow up.</time_frame>
    <description>Duration of hospitalisation recorded between start of conditioning regimen and 1 year post transplantation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of Life (QoL) assessment (FACT-BMT Questionnaire)</measure>
    <time_frame>Collected at baseline, Day 100, Month 12, Month 24, Month 36, Month 48 and Month 60 for each patient. The outcome will be analysed when the last patient has completed 2 years of follow up.</time_frame>
    <description>FACT-BMT Questionnaire uses Units on a scale 0-4. It measures quality of life, with 0 being the lowest quality of life and 4 being the highest quality of life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of Life (QoL) assessment (Short Form 36 Health Survey)</measure>
    <time_frame>Collected at baseline, Day 100, Month 12, Month 24, Month 36, Month 48 and Month 60 for each patient. The outcome will be analysed when the last patient has completed 2 years of follow up.</time_frame>
    <description>Short Form 36 Health Survey uses Units on a scale 1-6. Question 1 &amp; 2 consider general health (1 = best health score, 5 = worst). Question 3 considers activity level (1= least active, 3 = most). Question 4/5 considers work (1= work affected, 2= work not affected). Question 6 considers quality of relationships (1=not affected, 5 = most affected). Question 7 considers pain (1= no pain, 6 = worst). Question 8 considers housework/ paid work (1= not affected, 5= most affected). Question 9 considers mental health (1= best mental health, 6= worst). Question 10 considers social activities (1=most affected, 5= least affected). Question 11 considers self perception (1= worst, 5= best)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Full donor chimerism</measure>
    <time_frame>The outcome will be analysed when all patients have completed 100 days follow up.</time_frame>
    <description>Number of patients with full donor chimerism at day 100 Follow Up (for each patient)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Occurrence and severity of TBI related symptomatic pulmonary toxicity</measure>
    <time_frame>Collected in first 12 months from start of treatment</time_frame>
    <description>Collected using CTCAE 4.0 criteria</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Correlation of multi-lineage chimerism and relapse</measure>
    <time_frame>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</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Correlation of Minimal Residual Disease (MRD) with relapse</measure>
    <time_frame>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</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">242</enrollment>
  <condition>Acute Lymphoblastic Leukemia</condition>
  <arm_group>
    <arm_group_label>Fludarabine / Melphalan / Alemtuzumab</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <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 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</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cyclophosphamide / TBI (8Gy)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fludarabine</intervention_name>
    <description>IV</description>
    <arm_group_label>Fludarabine / Melphalan / Alemtuzumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Melphalan</intervention_name>
    <description>IV</description>
    <arm_group_label>Fludarabine / Melphalan / Alemtuzumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Alemtuzumab</intervention_name>
    <description>IV</description>
    <arm_group_label>Cyclophosphamide / TBI (8Gy)</arm_group_label>
    <arm_group_label>Fludarabine / Melphalan / Alemtuzumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>IV</description>
    <arm_group_label>Cyclophosphamide / TBI (8Gy)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Mesna</intervention_name>
    <description>IV</description>
    <arm_group_label>Cyclophosphamide / TBI (8Gy)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Total Body Irradiation (8Gy)</intervention_name>
    <description>TBI (8Gy)</description>
    <arm_group_label>Cyclophosphamide / TBI (8Gy)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients between the ages of 40-70 years. NB: Patients under the age of 40 who are&#xD;
             considered unsuitable for a myeloablative transplant may enrol onto the trial&#xD;
             following discussion with the CI via the Trials Office&#xD;
&#xD;
          -  Patients with ALL in first or second CR&#xD;
&#xD;
          -  Availability of a human leukocyte antigen (HLA) identical sibling or suitable matched&#xD;
             donor (suitable matched defined as no greater than a single allele mismatch at HLA A,&#xD;
             B, C or DRβ1). A single allele mismatch is permitted if there are adverse cytogenetics&#xD;
             or MRD positivity at any timepoint&#xD;
&#xD;
          -  Patients considered suitable to undergo a RIC allogeneic SCT as clinically judged by&#xD;
             the Local Investigator including:-&#xD;
&#xD;
               -  Adequate hepatic and renal function as determined by full blood count and&#xD;
                  biochemistry assessment&#xD;
&#xD;
               -  Resolution of any toxic effects of prior therapy (including radiotherapy,&#xD;
                  chemotherapy or surgical procedures). Patients with bone marrow suppression&#xD;
                  following therapy may enter the trial&#xD;
&#xD;
               -  Patients with abnormal cardiac and/or pulmonary function must be considered fit&#xD;
                  for allogeneic SCT including 8Gy of TBI at the time of randomisation.&#xD;
&#xD;
          -  Patients with an ECOG performance status 0,1 or 2&#xD;
&#xD;
          -  Females of and male patients of reproductive potential (i.e., not post-menopausal or&#xD;
             surgically sterilised) must use appropriate, highly effective, contraception from the&#xD;
             point of admission for transplant conditioning therapy until 12 months after&#xD;
             transplant (see section 8.1.2.2)&#xD;
&#xD;
          -  Patients have given written informed consent&#xD;
&#xD;
          -  Patients willing and able to comply with scheduled study visits and laboratory tests&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with contraindications to receiving RIC allogeneic SCT&#xD;
&#xD;
          -  Female patients who are pregnant or breastfeeding. All women of childbearing potential&#xD;
             (WOCBP) must have a negative pregnancy test before commencing treatment&#xD;
&#xD;
          -  Adults of reproductive potential not willing to use appropriate, effective,&#xD;
             contraception during the specified period&#xD;
&#xD;
          -  Patients with renal or hepatic impairment as clinically judged by Local Investigator&#xD;
&#xD;
          -  Patients with active infection, HIV-positive or chronic active Hep-A or -C&#xD;
&#xD;
          -  Patients with concurrent active malignancy. Patients with a previous history of&#xD;
             malignancy can be included if that malignancy is considered to be at a low risk of&#xD;
             recurrence&#xD;
&#xD;
          -  Previous exposure to a high dose of radiotherapy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David Marks</last_name>
    <role>Study Chair</role>
    <affiliation>Bristol Haeamatology and Oncology Centre</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Heart of England Nhs Foundation Trust</name>
      <address>
        <city>Birmingham</city>
        <zip>B95ST</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospitals Birmingham Nhs Foundation Trust</name>
      <address>
        <city>Birmingham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospitals Bristol Nhs Foundation Trust</name>
      <address>
        <city>Bristol</city>
        <zip>BS13NU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cambridge University Hospitals Nhs Foundation Trust</name>
      <address>
        <city>Cambridge</city>
        <zip>CB20QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cardiff and Vale University Health Board</name>
      <address>
        <city>Cardiff</city>
        <zip>CF144XW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NHS Greater Glasgow and Clyde</name>
      <address>
        <city>Glasgow</city>
        <zip>G12 0YN</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Leeds Teaching Hospitals Nhs Trust</name>
      <address>
        <city>Leeds</city>
        <zip>LS9 7TF</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospitals of Leicester Nhs Trust</name>
      <address>
        <city>Leicester</city>
        <zip>LE15WW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Clatterbridge Cancer Centre Nhs Foundation Trust</name>
      <address>
        <city>Liverpool</city>
        <zip>CH634JY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Barts Health Nhs Trust</name>
      <address>
        <city>London</city>
        <zip>E11BB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University College London Hospitals Nhs Foundation Trust</name>
      <address>
        <city>London</city>
        <zip>NW12PG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kings College Hospital</name>
      <address>
        <city>London</city>
        <zip>SE5 9RS</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Royal Marsden Nhs Foundation Trust</name>
      <address>
        <city>London</city>
        <zip>SW3 6JJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Imperial College Healthcare Nhs Trust</name>
      <address>
        <city>London</city>
        <zip>W21NY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Christie Nhs Foundation Trust</name>
      <address>
        <city>Manchester</city>
        <zip>M204BX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Central Manchester University Hospitals Nhs Foundation Trust</name>
      <address>
        <city>Manchester</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Newcastle Upon Tyne Hospitals Nhs Foundation Trust</name>
      <address>
        <city>Newcastle</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nottingham University Hospitals Nhs Trust</name>
      <address>
        <city>Nottingham</city>
        <zip>NG72UH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oxford University Hospitals Nhs Foundation Trust</name>
      <address>
        <city>Oxford</city>
        <zip>OX3 9DU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Plymouth Hospitals Nhs Trust</name>
      <address>
        <city>Plymouth</city>
        <zip>PL68DH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sheffield Teaching Hospitals Nhs Foundation Trust</name>
      <address>
        <city>Sheffield</city>
        <zip>S57AU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Southampton Nhs Foundation Trust</name>
      <address>
        <city>Southampton</city>
        <zip>SO16 6YD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>January 9, 2019</study_first_submitted>
  <study_first_submitted_qc>January 28, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 30, 2019</study_first_posted>
  <last_update_submitted>May 12, 2023</last_update_submitted>
  <last_update_submitted_qc>May 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Melphalan</mesh_term>
    <mesh_term>Fludarabine</mesh_term>
    <mesh_term>Alemtuzumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03821610
org study id: RG_17-241
nct id: NCT03821610
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Disease Free Survival (DFS)
time frame: The main analysis will take place once all patients have completed 2 years of follow up.
description: 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.
measure: Overall Survival (OS)
time frame: 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
description: 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
measure: Cumulative Incidence of Relapse (CIR)
time frame: 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
description: 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
measure: Non-relapse mortality (NRM)
time frame: 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
description: 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 aliveIncidence of Grade 2-4 acute GvHD within 100 days of transplant
measure: Incidence of chronic GvHD of any grade at 2 years
time frame: 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
measure: Occurrence and severity of VOD (Veno-occlusive disease) in the first 100 days
time frame: 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
measure: Duration of hospitalisation
time frame: The outcome will be conducted when all patients have completed 1 year of follow up.
description: Duration of hospitalisation recorded between start of conditioning regimen and 1 year post transplantation.
measure: Quality of Life (QoL) assessment (FACT-BMT Questionnaire)
time frame: Collected at baseline, Day 100, Month 12, Month 24, Month 36, Month 48 and Month 60 for each patient. The outcome will be analysed when the last patient has completed 2 years of follow up.
description: FACT-BMT Questionnaire uses Units on a scale 0-4. It measures quality of life, with 0 being the lowest quality of life and 4 being the highest quality of life.
measure: Quality of Life (QoL) assessment (Short Form 36 Health Survey)
time frame: Collected at baseline, Day 100, Month 12, Month 24, Month 36, Month 48 and Month 60 for each patient. The outcome will be analysed when the last patient has completed 2 years of follow up.
description: Short Form 36 Health Survey uses Units on a scale 1-6. Question 1 & 2 consider general health (1 = best health score, 5 = worst). Question 3 considers activity level (1= least active, 3 = most). Question 4/5 considers work (1= work affected, 2= work not affected). Question 6 considers quality of relationships (1=not affected, 5 = most affected). Question 7 considers pain (1= no pain, 6 = worst). Question 8 considers housework/ paid work (1= not affected, 5= most affected). Question 9 considers mental health (1= best mental health, 6= worst). Question 10 considers social activities (1=most affected, 5= least affected). Question 11 considers self perception (1= worst, 5= best)
measure: Full donor chimerism
time frame: The outcome will be analysed when all patients have completed 100 days follow up.
description: Number of patients with full donor chimerism at day 100 Follow Up (for each patient)
measure: Occurrence and severity of TBI related symptomatic pulmonary toxicity
time frame: Collected in first 12 months from start of treatment
description: Collected using CTCAE 4.0 criteria
measure: Correlation of multi-lineage chimerism and relapse
time frame: 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
measure: Correlation of Minimal Residual Disease (MRD) with relapse
time frame: 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
arm group label: Fludarabine / Melphalan / Alemtuzumab
arm group type: Active Comparator
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 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
arm group label: Cyclophosphamide / TBI (8Gy)
arm group type: Experimental
description: 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
intervention type: Drug
intervention name: Fludarabine
description: IV
arm group label: Fludarabine / Melphalan / Alemtuzumab
intervention type: Drug
intervention name: Melphalan
description: IV
arm group label: Fludarabine / Melphalan / Alemtuzumab
intervention type: Drug
intervention name: Alemtuzumab
description: IV
arm group label: Cyclophosphamide / TBI (8Gy)
arm group label: Fludarabine / Melphalan / Alemtuzumab
intervention type: Drug
intervention name: Cyclophosphamide
description: IV
arm group label: Cyclophosphamide / TBI (8Gy)
intervention type: Drug
intervention name: Mesna
description: IV
arm group label: Cyclophosphamide / TBI (8Gy)
intervention type: Radiation
intervention name: Total Body Irradiation (8Gy)
description: TBI (8Gy)
arm group label: Cyclophosphamide / TBI (8Gy)
criteria: 
gender: All
minimum age: 40 Years
maximum age: 70 Years
healthy volunteers: No
last name: David Marks
role: Study Chair
affiliation: Bristol Haeamatology and Oncology Centre
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Leukemia, Lymphoid
mesh term: Cyclophosphamide
mesh term: Melphalan
mesh term: Fludarabine
mesh term: Alemtuzumab
sharing ipd: No