Clinical Trials /

A Treatment Study Protocol for Participants 1-45 Years With Acute Lymphoblastic Leukaemia

NCT04307576

Description:

ALLTogether collects the experience of previously successful treatment of children and young adults, with ALL from a number of well-renowned study groups into a new master protocol, which is both a comprehensive system for stratification and treatment of ALL in this age-group as well as the basis for several randomised and interventional trials included in the study-design.

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: A Treatment Study Protocol for Participants 1-45 Years With Acute Lymphoblastic Leukaemia
  • Official Title: ALLTogether1 - A Treatment Study Protocol of the ALLTogether Consortium for Children and Young Adults (1-45 Years of Age) With Newly Diagnosed Acute Lymphoblastic Leukaemia (ALL)

Clinical Trial IDs

  • ORG STUDY ID: ALLTogether1
  • NCT ID: NCT04307576

Conditions

  • Leukemia, Acute Lymphoblastic

Interventions

DrugSynonymsArms
Omitted DoxorubicinR1 - SR experimental arm
Omitted Vincristine+Dexamethasone pulsesR2 - IR-low experimental arm
Inotuzumab Ozogamicin+Standard Maintenance TherapyBesponsa+Maintenance TherapyR3 - IR-high experimental arm
ImatinibABL-class fusions intervention

Purpose

ALLTogether collects the experience of previously successful treatment of children and young adults, with ALL from a number of well-renowned study groups into a new master protocol, which is both a comprehensive system for stratification and treatment of ALL in this age-group as well as the basis for several randomised and interventional trials included in the study-design.

Detailed Description

      ALLTogether is a European clinical treatment study for acute lymphoblastic leukaemia (ALL) in
      children and young adults. The aims are to improve survival and quality of survival for
      children and young adults with ALL. In young people, ALL has excellent outcome with an
      overall survival of about 92% in children and 75% in young adults. However, patients still
      die of disease - from relapse because of under-treatment and a large fraction of patients are
      also over-treated: All patients risk treatment-related death and some suffer long-term
      side-effects or secondary cancer. To show improvement with such good survival, large
      populations are needed.

      Study groups from Sweden, Norway, Iceland, Denmark, Finland, Estonia and Lithuania (NOPHO),
      the UK (UKALL), the Netherlands (DCOG), Germany (COALL), Belgium (BSPHO), Portugal (SHOP),
      Ireland (PHOAI), and France (SFCE), have designed a common treatment protocol for children
      and young adults with ALL.

      The study has a complex clinical trial design with sub-protocols (the randomisations /
      intervention) connected to a master protocol. The master protocol consists of well
      established therapy-elements and in its design typical for current ALL therapy. The master
      protocol therapy is in the study design considered as standard of care (SOC) therapy for
      children and young adults with ALL.

      The study structure is defined by a master protocol onto which randomised and interventional
      sub-protocols as well as sub-studies may be added, run and stop in a modular fashion.

      The randomisations / intervention may identify therapy that is less toxic, but equally
      efficacious for sub-groups of patients and innovative therapy that may reduce relapses and
      death from ALL. In the master protocol, improved risk-stratification is likely to increase
      survival and reduce unnecessary toxicity and the introduction of therapeutic drug monitoring
      (TDM) of Asparaginase activity will make the use of Asparaginase more rational and efficient
      and may thus improve overall outcomes.

      The investigators hypothesise that patients stratified to the standard-risk group are
      over-treated. Therefore, it will be tested if the treatment can be safely reduced. In the R1
      randomisation, patients will be randomised to receiving the Delayed Intensification (DI)
      phase of therapy with or without the anthracycline Doxorubicin.

      A similar hypothesis of over-treatment will also be tested in patients stratified to the
      intermediate risk-low group. In the R2 randomisation patients will be randomly assigned to
      either removal of Doxorubicin during the DI phase or removal of Vincristine and Dexamethasone
      pulses during the maintenance phase or to the control group, which will be treated with
      Doxorubicin in DI as well as Vincristine and Dexamethasone pulses during maintenance.
      Patients will only be randomised once.

      Randomisation R1 and R2 are only considered for children since adults have worse outcome and
      very poor survival after relapse, but the risk-stratification is likely to reduce the number
      of high-risk cases also in the adult-group.

      Patients stratified as intermediate risk-high (IR-high) are identified as having an increased
      risk of relapse and thus a less favourable prognosis than the standard- and intermediate
      risk-low groups, but a more favourable prognosis than the high risk patients. The majority of
      all relapses in childhood ALL occur in the IR-high group. Following a relapse, 40 % of the
      children can be successfully treated again and for adults the corresponding figure is less
      than 20 %, so preventing relapses is very important. New treatment options that improves the
      antileukemic efficacy and which have an improved safety profile are urgently needed.

      For IR-high patients the R3 randomisation is available. In R3 patients will be randomised to
      the addition of two cycles of Inotuzumab ozogamicin (InO) - Besponsa®, before the start of
      the maintenance phase or no addition. The patients randomised to the InO arm will receive
      maintenance for the same duration as in the control arm.

      Patients with ABL-class fusions in their leukaemic clone will, as a non-randomised
      experimental intervention, be treated with an addition of a tyrosine-kinase inhibitor during
      the induction phase (for patients <25 years) and from the consolidation phase (patients ≥25
      years). This intervention may shift therapy for previously resistant cases to lower intensity
      treatment with the associated reduced morbidity and may also reduce the number of relapses in
      analogy with the results in Ph+ ALL. The reason for not performing a randomised comparison is
      the rarity of the aberration and also the diversity of ABL-class fusions, reducing
      statistical power for any comparison further. For this reason, the results of this
      intervention may be pooled with other study-groups trying similar approaches.

      For high-risk B-lineage patients, CAR-T therapy can be an alternative to high-risk blocks and
      stem-cell transplant, but in this case the intervention (CAR-T infusion) will be performed
      outside the ALLTogether1 study. However, the stratification-system in ALLTogether1 will
      define the population with a potential CAR-T indication.
    

Trial Arms

NameTypeDescriptionInterventions
R1 - SR standard armNo InterventionStandard risk arm receiving standard treatment (Delayed Intensification including Doxorubicin).
    R1 - SR experimental armExperimentalStandard risk arm, receiving Delayed Intensification without Doxorubicin IV 3 x 30 mg/m2/dose.
    • Omitted Doxorubicin
    R2 - IR-low standard armNo InterventionStandard treatment with Delayed Intensification including Doxorubicin and Maintenance including Vincristine+Dexamethasone pulses.
      R2 - IR-low experimental armExperimentalStandard treatment with omission of either (2 experimental arms) Doxorubicin IV 3 x 30 mg/m2/dose in the Delayed Intensification phase OR Monthly pulses of Vincristine IV 1,5 mg/m2/dose and 5 days of Dexamethasone p.o. 6 mg/m2/day in the Maintenance Phase.
      • Omitted Doxorubicin
      • Omitted Vincristine+Dexamethasone pulses
      R3 - IR-high standard armNo InterventionIntermediate risk high arm receiving Standard Maintenance Therapy.
        R3 - IR-high experimental armExperimentalInotuzumab IV 0,5 mg/m2, given on days 253, 260, 267 and on days 274, 281, 288 before start of Standard Maintenance Therapy.
        • Inotuzumab Ozogamicin+Standard Maintenance Therapy
        ABL-class fusions interventionExperimentalImatinib p.o. 340 mg/m2 given daily from day 15 or 30 (depending on age) to the end of therapy (week 106) in addition to standard IR-high chemotherapy.
        • Imatinib

        Eligibility Criteria

                Inclusion Criteria:
        
                  -  Patients newly diagnosed with T-lymphoblastic (T-cell) or B-lymphoblastic precursor
                     (BCP) leukaemia (ALL) according to the WHO-classification of Tumours of Haematopoetic
                     and Lymphoid Tissues (Revised 4th edition 2017) and with a diagnosis confirmed by an
                     accredited laboratory at a participating paediatric oncology or adult haematology
                     centre.
        
                  -  Age ≥ 365 days and < 46 years (one day before 46th birthday) at the time of diagnosis.
        
                  -  Informed consent signed by the patient and/or parents/legal guardians according to
                     country-specific age-related guidelines
                     (http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/12/WC500199234.pdf ).
        
                  -  The ALL diagnosis should be confirmed by an accredited laboratory at a participating
                     paediatric oncology or adult haematology centre.
        
                  -  The patient should be diagnosed and treated at a participating paediatric oncology or
                     adult haematology centre in the participating countries.
        
                  -  The patient should be a resident in one of the participating countries on a permanent
                     basis or should intend to settle in a participating country, for instance by an
                     application for asylum. Patients who are visiting the country as tourists should not
                     be included. However, returning expatriots with primary diagnosis abroad may be
                     included if no treatment has been administered and the diagnostic procedures are
                     repeated at a participating centre.
        
                  -  All women of childbearing potential (WOCBP) have to have a negative pregnancy test
                     within 2 weeks prior to the start of treatment.
        
                  -  For each intervention/randomisation an additional set of inclusion-criteria is
                     provided.
        
                Exclusion Criteria:
        
                  -  Age < 365 days at diagnosis (infant ALL) or >45 years at diagnosis.
        
                  -  Patients with a previous malignant diagnosis (ALL as a second malignant neoplasm -
                     SMN).
        
                  -  Relapse of ALL.
        
                  -  Patients with mature B-ALL (as defined by Surface Ig positivity or documented presence
                     of one of the t(8;14), t(2;8), t(8;22) translocations and breakpoint as in B-ALL).
        
                  -  Patients with Ph-positive ALL (documented presence of t(9;22)(q34;q11) and/or of the
                     BCR/ABL fusion transcript). These patients will be transferred to an adequate trial
                     for t(9;22) if available.
        
                  -  ALL prone syndromes (e.g. Li-Fraumeni syndrome, germline ETV6 mutation), except for
                     Down syndrome. Exploration for such ALL prone syndromes is not mandatory.
        
                  -  Treatment with systemic corticosteroids (>10mg/m2/day) for more than one week and/or
                     other chemotherapeutic agents in a 4-week interval prior to diagnosis (pre-treatment).
        
                  -  Pre-existing contraindications to any treatment according to the ALLTogether protocol
                     (constitutional or acquired disease prior to the diagnosis of ALL preventing adequate
                     treatment).
        
                  -  Any other disease or condition, as determined by the investigator, which could
                     interfere with the participation in the study according to the study protocol, or with
                     the ability of the patients to cooperate and comply with the study procedures.
        
                  -  Women of childbearing potential who are pregnant at the time of diagnosis.
        
                  -  Women of childbearing potential and fertile men who are sexually active and are
                     unwilling to use adequate contraception during therapy. Efficient birth control is
                     required.
        
                  -  Female patients, who are breast-feeding.
        
                  -  Essential data missing from the registration of characteristics at diagnosis (in
                     consultation with the protocol chair).
        
                  -  For each intervention/randomisation an additional set of exclusion-criteria is
                     provided.
              
        Maximum Eligible Age:45 Years
        Minimum Eligible Age:1 Year
        Eligible Gender:All
        Healthy Volunteers:No

        Primary Outcome Measures

        Measure:Event-free survival (EFS) for the whole protocol
        Time Frame:5 year estimates from the time of diagnosis will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
        Safety Issue:
        Description:The primary endpoint for the whole protocol (compared with the legacy protocols of the participating study-groups forming the consortium) is event-free survival (EFS) - as defined in the protocol.

        Secondary Outcome Measures

        Measure:Overall survival (OS) for the whole protocol
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
        Safety Issue:
        Description:Overall survival defined as time from diagnosis to death or end of follow-up for surviving patients.
        Measure:Overall survival (OS) for R1 + R2
        Time Frame:5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
        Safety Issue:
        Description:Overall survival defined as time from randomisation to death or end of follow-up for surviving patients.
        Measure:Overall survival (OS) for R3
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
        Safety Issue:
        Description:Overall survival defined as time from randomisation to death or end of follow-up for surviving patients
        Measure:Overall survival (OS) for TKI
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up (TKI).
        Safety Issue:
        Description:Overall survival defined as time from start of TKI to death or end of follow-up for surviving patients
        Measure:Induction death
        Time Frame:From diagnosis until death before remission (at the earliest, day 29) or in case of no CR day 29, completion of induction and consolidation 1 (protocol day 99 - Down) and in addition 3 high-risk blocks (protocol day 134 - all other patients)
        Safety Issue:
        Description:Fraction of patients who die as well as cumulative incidence of death before achieved complete remission (CR) within the time-frame described in the protocol
        Measure:Resistant disease
        Time Frame:From diagnosis until achieved complete remission (at the earliest, day 29) or in case of no CR day 29, assessment after induction and consolidation 1 (protocol day 99-Down patients) and in addition 3 high-risk blocks (protocol day 134-all other patients)
        Safety Issue:
        Description:Fraction of patients as well as cumulative incidence of resistant disease as described in the protocol. Induction death as competing risk.
        Measure:Cumulative incidence of relapse for the whole protocol
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
        Safety Issue:
        Description:Time from achieved complete remission until relapse as defined in the protocol or end of follow-up. Second malignancy, death in complete remission as competing events.
        Measure:Cumulative incidence of relapse for R1 + R2
        Time Frame:5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
        Safety Issue:
        Description:Time from randomisation until relapse as defined in the protocol or end of follow-up. Second malignancy, death in complete remission as competing events.
        Measure:Cumulative incidence relapse for R3
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
        Safety Issue:
        Description:Time from randomisation until relapse as defined in the protocol or end of follow-up. Second malignancy, death in complete remission as competing events.
        Measure:Cumulative incidence CD22 negative relapse for R3
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
        Safety Issue:
        Description:Time from randomisation until relapse without expression of CD22 as defined in the protocol or end of follow-up. Second malignancy, death in complete remission and relapse with CD22 expression as competing events.
        Measure:Cumulative incidence relapse for TKI
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up
        Safety Issue:
        Description:Time from start of TKI until relapse as defined in the protocol or end of follow-up. Second malignancy, death in complete remission as competing events.
        Measure:Second malignant neoplasm (SMN) for the whole protocol
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
        Safety Issue:
        Description:Time from achieved complete remission until diagnosis of second malignant neoplasm as defined in the protocol or end of follow-up. Relapse and death in complete remission as competing events.
        Measure:Secondary malignancy for R1+R2
        Time Frame:5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
        Safety Issue:
        Description:Time from randomisation until diagnosis of second malignant neoplasm as defined in the protocol or end of follow-up. Relapse and death in complete remission as competing events.
        Measure:Secondary malignancy for R3
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up.
        Safety Issue:
        Description:Time from randomisation until diagnosis of second malignant neoplasm as defined in the protocol or end of follow-up. Relapse and death in complete remission as competing events.
        Measure:Secondary malignancy for TKI
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
        Safety Issue:
        Description:Time from start of TKI until diagnosis of second malignant neoplasm as defined in the protocol or end of follow-up. Relapse and death in complete remission as competing events.
        Measure:Death in complete remission for the whole protocol
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
        Safety Issue:
        Description:Time from achieved complete remission until death in complete remission as defined in the protocol or end of follow-up. Relapse and second malignant neoplasm as competing events.
        Measure:Death in complete remission for R1+R2
        Time Frame:5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up.
        Safety Issue:
        Description:Time from randomisation until death in complete remission as defined in the protocol or end of follow-up. Relapse and second malignant neoplasm as competing events.
        Measure:Death in complete remission for R3
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
        Safety Issue:
        Description:Time from randomisation until death in complete remission as defined in the protocol or end of follow-up. Relapse and second malignant neoplasm as competing events.
        Measure:Death in complete remission for TKI
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up
        Safety Issue:
        Description:Time from start of TKI until death in complete remission as defined in the protocol or end of follow-up. Relapse and second malignant neoplasm as competing events.
        Measure:Treatment-related mortality for the whole protocol
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
        Safety Issue:
        Description:Time from diagnosis until death during induction, death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).
        Measure:Treatment-related mortality R1+R2
        Time Frame:5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up.
        Safety Issue:
        Description:Time from randomisation until death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).
        Measure:Treatment-related mortality R3
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
        Safety Issue:
        Description:Time from randomisation until death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).
        Measure:Treatment-related mortality TKI
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up
        Safety Issue:
        Description:Time from start of TKI until death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).
        Measure:Leukaemia specific mortality for the whole protocol
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
        Safety Issue:
        Description:Time from diagnosis until death after resistant disease or relapse - as defined in the protocol.
        Measure:Leukaemia specific mortality for R1+R2
        Time Frame:5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
        Safety Issue:
        Description:Time from randomisation until death after relapse - as defined in the protocol.
        Measure:Leukaemia specific mortality for R3
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
        Safety Issue:
        Description:Time from randomisation until death after relapse - as defined in the protocol.
        Measure:Leukaemia specific mortality for TKI
        Time Frame:5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up
        Safety Issue:
        Description:Time from start of TKI until death after relapse - as defined in the protocol.
        Measure:Incidence of Adverse Events of Special Interest (AESIs) per treatment-phase in the whole protocol and TKI intervention
        Time Frame:From time of diagnosis after each treatment-phase (one extra in the middle of maintenance) and annually until 5 years from discontinuation of therapy.
        Safety Issue:
        Description:Cumulative incidence of 19 AESIs as defined in the protocol
        Measure:Incidence of Adverse Events of Special Interest (AESIs) extra assessment (R1+R2)
        Time Frame:From time of randomisation, assessment after delayed intensification and 3 months after start of maintenance (R1+R2) and 4 times during maintenance (R2)
        Safety Issue:
        Description:Cumulative incidence of 4 additional AESIs as defined in the protocol
        Measure:Incidence of Adverse Events of Special Interest (AESIs) extra assessment (R3)
        Time Frame:From time of randomisation assessment after the randomised phase (12 weeks into maintenance for controls) and 4 times during maintenance
        Safety Issue:
        Description:Cumulative incidence of 3 additional AESIs as defined in the protocol
        Measure:Incidence of Serious Adverse Events (SAEs) and Adverse Events (AEs) related to R3
        Time Frame:From time of randomisation until the end of maintenance therapy
        Safety Issue:
        Description:Cumulative incidence of SAEs and AEs (with limitations) as defined in the protocol
        Measure:Quantitative measures of toxicity R1+R2
        Time Frame:From time of randomisation, assessment after delayed intensification and 6 weeks after start of maintenance
        Safety Issue:
        Description:Days: in hospital, with iv antibiotics, with iv analgesics, with iv nutritional support
        Measure:Metabolic consequences of steroid exposure (R2)
        Time Frame:At the end of therapy and 5 years after discontinuation of treatment
        Safety Issue:
        Description:Measurements of BMI

        Details

        Phase:Phase 3
        Primary Purpose:Interventional
        Overall Status:Not yet recruiting
        Lead Sponsor:Mats Heyman

        Trial Keywords

        • Leukemia
        • Acute Leukemia
        • ALL
        • ALLTogether
        • Leukaemia
        • Inotuzumab ozogamicin
        • Besponsa
        • ALLTogether1

        Last Updated

        March 12, 2020