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Trial record 1 of 1 for:    NCT04307576
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A Treatment Study Protocol for Participants 1-45 Years With Acute Lymphoblastic Leukaemia

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ClinicalTrials.gov Identifier: NCT04307576
Recruitment Status : Recruiting
First Posted : March 13, 2020
Last Update Posted : January 5, 2021
Sponsor:
Collaborators:
The Swedish Research Council
The Swedish Childhood Cancer Foundation
Pfizer
Servier
NordForsk
Aamu Pediatric Cancer Foundation
Gesellschaft fur Padiatrische Onkologie und Hamatologie - Germany
Clinical Trial Center North (CTC North GmbH & Co. KG)
Belgium Health Care Knowledge Centre
Karolinska Institutet
Cancer Research UK
Fundação Rui Osório de Castro
Acreditar - Associação de Pais e Amigos das Crianças com Cancro
Grupo Português De Leucemias Pediátricas
Amgen
Nova Laboratories Limited
Danish Child Cancer Foundation
Danish Cancer Society
The Novo Nordic Foundation
Information provided by (Responsible Party):
Mats Heyman, Karolinska University Hospital

Tracking Information
First Submitted Date  ICMJE March 5, 2020
First Posted Date  ICMJE March 13, 2020
Last Update Posted Date January 5, 2021
Actual Study Start Date  ICMJE July 14, 2020
Estimated Primary Completion Date June 30, 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 2, 2020)
  • 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. ]
    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.
  • Event-free survival (EFS) for the TKI intervention [ Time Frame: From the start of TKI (day 15 or day 30), 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up for all interventions except Inotuzumab-randomisation (minimum 2-year follow-up). ]
    The primary endpoint for the TKI intervention is event-free survival (EFS) - as defined in the protocol, from the start of TKI until event or end of follow-up
  • Disease-free survival (DFS) R1 + R2 [ Time Frame: 5 and 8 year estimates from the time of randomisation will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up. ]
    The primary endpoint for Randomisation 1 and 2 is disease-free survival (DFS) - as defined in the protocol counting from the time of randomisation
  • Disease-free survival (DFS) R3 [ Time Frame: 5 year estimates from the time of randomisation will be measured but adequate follow-up for these estimates will be ensured: at least 2-year follow-up ]
    The primary endpoint for Randomisation 3 and the ABL-class fusion intervention is disease-free survival (DFS) - as defined in the protocol counting from the time of randomisation (R3) and the start of TKI-therapy (ABL-class fusion intervention).
  • MRD response after 1 cycle of Blinatumomab [ Time Frame: End of first Blinatumomab infusion +/- 1 week ]
    Fraction of patients with undetectable MRD ("Complete MRD response") at the end of one cycle of Blinatumomab (+/- 1 week)
Original Primary Outcome Measures  ICMJE
 (submitted: March 12, 2020)
  • 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. ]
    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.
  • Event-free survival (EFS) for the TKI intervention [ Time Frame: From the start of TKI (day 15 or day 30), 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up for all interventions except Inotuzumab-randomisation (minimum 2-year follow-up). ]
    The primary endpoint for the TKI intervention is event-free survival (EFS) - as defined in the protocol, from the start of TKI until event or end of follow-up
  • Disease-free survival (DFS) R1 + R2 [ Time Frame: 5 and 8 year estimates from the time of randomisation will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up. ]
    The primary endpoint for Randomisation 1 and 2 is disease-free survival (DFS) - as defined in the protocol counting from the time of randomisation
  • Disease-free survival (DFS) R3 [ Time Frame: 5 year estimates from the time of randomisation will be measured but adequate follow-up for these estimates will be ensured: at least 2-year follow-up ]
    The primary endpoint for Randomisation 3 and the ABL-class fusion intervention is disease-free survival (DFS) - as defined in the protocol counting from the time of randomisation.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 2, 2020)
  • 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. ]
    Overall survival defined as time from diagnosis to death or end of follow-up for surviving patients.
  • 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. ]
    Overall survival defined as time from randomisation to death or end of follow-up for surviving patients.
  • 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 ]
    Overall survival defined as time from randomisation to death or end of follow-up for surviving patients.
  • Overall survival (OS) for R3-TEAM associated with DNA-TG [ Time Frame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up ]
    Overall survival as defined above in relation to DNA-TG.
  • 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). ]
    Overall survival defined as time from start of TKI to death or end of follow-up for surviving patients
  • Overall survival (OS) for ALLTogether1 DS [ Time Frame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up. ]
    Overall survival defined as time from start of Blinatumomab to death or end of follow-up for surviving patients
  • 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) ]
    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
  • 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) ]
    Fraction of patients as well as cumulative incidence of resistant disease as described in the protocol. Induction death as competing risk.
  • 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. ]
    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.
  • 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. ]
    Time from randomisation until relapse as defined in the protocol or end of follow-up. Second malignancy, death in complete remission as competing events.
  • 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 ]
    Time from randomisation until relapse as defined in the protocol or end of follow-up. Second malignancy, death in complete remission as competing events.
  • Cumulative incidence relapse for R3-TEAM in association with DNA-TG [ Time Frame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up ]
    Cumulative incidence of relapse as defined for R3 in association with DNA-TG for R3-TEAM. Second malignancy, death in complete remission as competing events.
  • 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 ]
    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.
  • 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 ]
    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.
  • Cumulative incidence relapse for ALLTogether1 DS [ Time Frame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up ]
    Time from start of Blinatumomab until relapse as defined in the protocol or end of follow-up. Second malignancy, death in complete remission as competing events.
  • Cumulative incidence of CD19 negative relapse for ALLTogether1 DS [ Time Frame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up ]
    Time from start of Blinatumomab until CD19 negative relapse as defined in the protocol or end of follow-up. Second malignancy, death in complete remission and CD19 positive relapse as competing events.
  • Cumulative incidence of 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. ]
    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.
  • Cumulative incidence of second 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. ]
    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.
  • Cumulative incidence of second 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. ]
    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.
  • Cumulative incidence of second malignancy for R3-TEAM in association with DNA-TG [ Time Frame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up. ]
    Cumulative incidence of second malignancy as defined above for R3 in association with DNA-TG for R3-TEAM. Relapse and death in complete remission as competing events.
  • Cumulative incidence of second 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. ]
    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.
  • Cumulative incidence of second malignancy for ALLTogether1 DS [ Time Frame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up. ]
    Time from start of Blinatumomab 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.
  • Cumulative incidence of 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. ]
    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.
  • Cumulative incidence of 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. ]
    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.
  • Cumulative incidence of 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 ]
    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.
  • Cumulative incidence of 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 ]
    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.
  • Cumulative incidence of death in complete remission for ALLTogether1 DS [ Time Frame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up ]
    Time from start of Blinatumomab until death in complete remission as defined in the protocol or end of follow-up. Relapse and second malignant neoplasm as competing events.
  • Cumulative incidence of 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. ]
    Time from diagnosis until death during induction, death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).
  • Cumulative incidence of 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. ]
    Time from randomisation until death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).
  • Cumulative incidence of 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 ]
    Time from randomisation until death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).
  • Cumulative incidence of 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 ]
    Time from start of TKI until death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).
  • 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. ]
    Time from diagnosis until death after resistant disease or relapse - as defined in the protocol.
  • 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. ]
    Time from randomisation until death after relapse - as defined in the protocol.
  • 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 ]
    Time from randomisation until death after relapse - as defined in the protocol.
  • 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 ]
    Time from start of TKI until death after relapse - as defined in the protocol.
  • 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. ]
    Cumulative incidence of 19 AESIs as defined in the protocol
  • Incidence of Adverse Events of Special Interest (AESIs) extra assessment (R1+R2) [ Time Frame: Cumulative incidence of AESIs estimated 3 months after start of maintenance (R1+R2) and at the end of maintenance (R2) ]
    Cumulative incidence of 4 additional AESIs as defined in the protocol
  • Incidence of Adverse Events of Special Interest (AESIs) extra assessment (R3) [ Time Frame: Cumulative incidence of AESIs estimated at the end of maintenance. ]
    Cumulative incidence of 3 additional AESIs as defined in the protocol
  • 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 (approximately 77 weeks from randomisation) ]
    Cumulative incidence of SAEs and AEs (with limitations) as defined in the protocol
  • Quantitative measures of toxicity R1+R2 [ Time Frame: From time of randomisation, assessment after delayed intensification and 6 weeks after start of maintenance ]
    Days: in hospital, with iv antibiotics, with iv analgesics, with iv nutritional support
  • Metabolic consequences of steroid exposure (R2) [ Time Frame: At the end of therapy (approximately 94 weeks from randomisation) and 5 years after discontinuation of treatment ]
    Measurements of BMI
  • Association of Disease-free survival (DFS) with DNA-TG for R3-TEAM [ Time Frame: 5 year estimates from the time of randomisation will be measured but adequate follow-up for these estimates will be ensured: at least 2-year follow-up ]
    Disease-free survival (DFS) - as defined above associated with DNA-TG.
  • Cumulative incidence of Sinusoidal Obstruction Syndrome (SOS) and Nodular Regenerative Hyperplasia (NRH) for R3-TEAM [ Time Frame: Cumulative incidence of SOS/NRH estimated at the end of follow-up. ]
    Time from randomisation until diagnosis of SOS or NRH as defined in the protocol or end of follow-up.
  • Cumulative incidence of Osteonecrosis for R3-TEAM [ Time Frame: Cumulative incidence of osteonecrosis estimated at the end of follow-up. ]
    Time from randomisation until diagnosis of osteonecrosis as defined in the protocol or end of follow-up.
  • Event-free survival (EFS) for ALLTogether1 DS [ Time Frame: From the start of Blinatumomab, 5 year estimate will be measured but adequate follow-up for this estimate will be ensured: at least 5 years follow-up. ]
    Event-free survival as defined in the protocol, from the start of Blinatumomab until death from any cause, relapse, second malignancy, protocol therapy failure (MRD>1% after 2 cycles blinatumomab and Augmented BFM consolidation) or end of follow-up.
  • Incidence of Blinatumomab refractory disease for ALLTogether1 DS [ Time Frame: From the start of Blinatumomab until end of 2nd cycle of Blinatumomab (each cycle is 4 weeks followed by a 2-week treatment free period) ]
    Incidence of progressive disease under Blinatumomab treatment or MRD ≥1% at the end of the 2nd cycle of Blinatumomab.
  • Incidence of Protocol Therapy Failure for ALLTogether1 DS [ Time Frame: From the start of Blinatumomab until the end of Consolidation 1 (85-140 days: 15-70 days of Blinatumomab therapy + 70 days of Consolidation 1) ]
    Incidence of patients who have MRD ≥1 % post 2 cycles of Blinatumomab followed by Augmented BFM consolidation, corresponding to original protocol day 99, or unchanged/increasing MRD during Augmented BFM consolidation corresponding to original protocol day 57.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 12, 2020)
  • 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. ]
    Overall survival defined as time from diagnosis to death or end of follow-up for surviving patients.
  • 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. ]
    Overall survival defined as time from randomisation to death or end of follow-up for surviving patients.
  • 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 ]
    Overall survival defined as time from randomisation to death or end of follow-up for surviving patients
  • 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). ]
    Overall survival defined as time from start of TKI to death or end of follow-up for surviving patients
  • 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) ]
    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
  • 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) ]
    Fraction of patients as well as cumulative incidence of resistant disease as described in the protocol. Induction death as competing risk.
  • 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. ]
    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.
  • 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. ]
    Time from randomisation until relapse as defined in the protocol or end of follow-up. Second malignancy, death in complete remission as competing events.
  • 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 ]
    Time from randomisation until relapse as defined in the protocol or end of follow-up. Second malignancy, death in complete remission as competing events.
  • 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 ]
    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.
  • 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 ]
    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.
  • 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. ]
    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.
  • 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. ]
    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.
  • 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. ]
    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.
  • 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. ]
    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.
  • 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. ]
    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.
  • 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. ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
  • 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. ]
    Time from diagnosis until death during induction, death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).
  • 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. ]
    Time from randomisation until death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).
  • 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 ]
    Time from randomisation until death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).
  • 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 ]
    Time from start of TKI until death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).
  • 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. ]
    Time from diagnosis until death after resistant disease or relapse - as defined in the protocol.
  • 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. ]
    Time from randomisation until death after relapse - as defined in the protocol.
  • 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 ]
    Time from randomisation until death after relapse - as defined in the protocol.
  • 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 ]
    Time from start of TKI until death after relapse - as defined in the protocol.
  • 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. ]
    Cumulative incidence of 19 AESIs as defined in the protocol
  • 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) ]
    Cumulative incidence of 4 additional AESIs as defined in the protocol
  • 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 ]
    Cumulative incidence of 3 additional AESIs as defined in the protocol
  • 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 ]
    Cumulative incidence of SAEs and AEs (with limitations) as defined in the protocol
  • Quantitative measures of toxicity R1+R2 [ Time Frame: From time of randomisation, assessment after delayed intensification and 6 weeks after start of maintenance ]
    Days: in hospital, with iv antibiotics, with iv analgesics, with iv nutritional support
  • Metabolic consequences of steroid exposure (R2) [ Time Frame: At the end of therapy and 5 years after discontinuation of treatment ]
    Measurements of BMI
Current Other Pre-specified Outcome Measures
 (submitted: November 2, 2020)
  • 6-mercaptopurine and Methotrexate metabolite pharmacokinetics (i.e. Ery-TGN/MeMP/MTXpg) for R3-TEAM [ Time Frame: From start of Maintenance therapy until the end of Maintenance therapy (protocol week 37 until protocol week 108) ]
    Measurements of metabolites Ery-TGN/MeMP/MTXpg during Maintenance therapy.
  • Abnormal liver function parameters (including hypoglycemia) for R3-TEAM [ Time Frame: From start of Maintenance therapy until the end of Maintenance therapy (protocol week 37 until protocol week 108) ]
    Liver function parameters including hypoglycemia during Maintenance therapy
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Treatment Study Protocol for Participants 1-45 Years With Acute Lymphoblastic Leukaemia
Official Title  ICMJE 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)
Brief Summary 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 is expected to occur in the IR-high group. Following a relapse, only approximately 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 antileukaemic efficacy and which have an improved safety profile are urgently needed.

For IR-high patients Randomisation 3 (R3) is available. In R3 patients will be randomised to receive either:

  1. the addition of two cycles of Inotuzumab ozogamicin (InO) - Besponsa®, before start of the maintenance phase. After these cycles, the patients randomised to the InO arm will receive maintenance for the same duration as in the control arm.
  2. the addition of low dose 6-tioguanine (6TG) as an addition to the standard maintenance therapy.
  3. standard maintenance therapy

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.

A new intervention is introduced for Down syndrome patients with CD19 positive ALL: ALLTogether1 DS (NRI2). For Down syndrome-ALL patients who have end of Induction MRD detectable but <25% two conventional chemotherapy consolidation blocks will be replaced with two blocks of Blinatumomab.

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.

ALLTogether1 also includes five sub-studies:

Efficacy of Imatinib in ABL-class fusion positive ALL

Target population: All ABL-class patients enrolled in the ALLTogether study. Biomaterials to be collected at diagnosis, follow-up and relapse.

Aims

  1. To determine the efficacy of imatinib in the treatment of ABL-class leukemia
  2. To find the best discriminative biomarkers for TKI response in ABL-class ALL
  3. To determine the frequency of intrinsic (at diagnosis) and acquired TKI resistance (due to treatment)
  4. To find causes of TKI resistance in ABL-class patients

Objectives

  1. To determine the percent of ABL-class patients who need to switch from IR-high to HR because of high MRD levels
  2. To determine the effect of imatinib exposure on clinical outcome
  3. To determine the molecular response to imatinib by monitoring fusion transcript levels and mutational spectrum at diagnosis and during follow up
  4. To determine whether the molecular response parameters reflect the Ig/TCR MRD or flow-MRD response or are a better predictor of therapy failure than Ig/TCR or flow-based MRD monitoring
  5. To determine the phosphorylation status of ABL-class proteins and presence of TKI-resistance associated mutations in ABL genes prior to imatinib treatment and the emergence of such mutations during treatment with imatinib
  6. To determine the presence of mutations in regulatory /other genes before and during imatinib treatment and functionally address the importance of these mutations in TKI resistance
  7. To determine whether the efficacy of TKIs depends on the type of fusion gene

Biomarkers to Reform Approaches to therapy-Induced Neurotoxicity (BRAIN)

Target population: All patients registered on ALLTogether1 aged ≥ 4 years at end of therapy and without:

  1. Pre-existing neurodevelopmental disorder (e.g Trisomy 21, ADHD) prior to diagnosis of ALL
  2. Significant visual or motor impairment preventing use of a touch screen ipad

Aims

  1. To institute universal screening of all children for adverse neurocognitive outcomes at the end of treatment using a validated user-friendly computer software programme (CogState) and compare neurocognitive outcomes by treatment allocation.
  2. To identify risk factors for adverse outcomes including whether acute neurotoxic events are associated with poor performance on cognitive tests at end of therapy compared to patients without acute neurotoxicity.

Primary end-point

a. Proportion of children with a z-score <1.5 on detection and/or identification CogState tasks in each treatment arm at the end of anti-leukaemic therapy. A z-score < 1.5 correlates with moderate cognitive impairment at a level that may require additional support.

Secondary and exploratory end-points

  1. Association between CogState scores at end of treatment and overt neurotoxic episodes as recorded on the trial adverse event database.
  2. Association between Cogstate scores and clinical and demographic variables - age, sex, ethnicity, CNS status.
  3. Proportion of children with scores <1.5SD for one card learning (learning), one back (working memory) and Groton's maze (executive function) on different treatment arms.
  4. Association between CogState scores and patient reported outcome measures/Quality of life measurements collected as part of the main ALLTogether1 trial.

Association between asparaginase activity levels and outcome

Target population: All patients included in the ALLTogether1 protocol are eligible for participation.

Primary aim

To study the association between asparaginase activity levels and outcome (MRD, relapse, survival)

Secondary aims

  1. To evaluate the association between asparaginase activity levels and toxicities, such as pancreatitis, infections and deep venous thrombosis (DVT)
  2. To evaluate the association between asparaginase activity levels and hepatotoxicity in a subset of patients

CSF-Flow

Target population: All patients included in the ALLTogether1 protocol are eligible for participation

Aims

  1. To use cerebrospinal fluid (CSF) flow cytometry (FCM) to improve the accuracy of diagnostic tests for CNS leukaemia compared to conventional CSF cytology. An associated objective will be to develop a recommended protocol for CSF flow cytometry with external quality assessment to ensure uniformity of measurement across the ALLTogether consortium.
  2. To investigate whether negative FCM identifies a group of children at very low risk of CNS relapse, suitable for testing de-escalation of CNS-directed therapy in future trials.
  3. To investigate whether positive FCM can identify children at increased risk of CNS relapse and whether patients with persistent positivity (FCM positive at day 15 onwards) might benefit from studies testing escalated CNS-directed therapy or a switch to more intensive treatment arms.
  4. To collect matching CSF supernatant for studies comparing CSF FCM with soluble biomarkers (e.g. metabolic, cell-free DNA, proteomic and microRNA) in selected centres.

Maintenance therapy pharmacokinetics/-dynamics study

Target population: All patients included in the ALLTogether1 protocol are eligible for participation. For IR-high patients participating in the randomised InO- and TEAM sub-protocols, the monitoring of 6-mercaptopurine (6MP)/Methotrexate (MTX) metabolites at three months intervals is mandatory.

Aims and specific objectives

  1. To map pharmacokinetics of 6MP and MTX during maintenance therapy in all patients in the ALLTogether protocol.
  2. To associate metabolite profiles with TPMT and NUDT15 variants, as routinely analysed in ALLTogether.
  3. To explore the association of event-free survival with DNA-TG and other 6MP/MTX metabolites.
  4. To explore the association between risk of second cancers with DNA-TG and other 6MP/MTX metabolites.
  5. To explore the association of risk of invasive infections with DNA-TG and other 6MP/MTX metabolites.
  6. To explore the association of risk of osteonecrosis with DNA-TG and other 6MP/MTX metabolites.
  7. To explore the association of sinusoidal obstruction syndrome with DNA-TG and other 6MP/MTX metabolites.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
Master protocol with risk-stratification. The risk-stratified groups will proceed to non-randomised or randomised interventions in single arm (TKI) and (Blinatumomab) and parallel (R1/R2/R3) models respectively.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Leukemia, Acute Lymphoblastic
Intervention  ICMJE
  • Drug: Omitted Doxorubicin
    Omission of IV Doxorubicin
  • Drug: Omitted Vincristine+Dexamethasone pulses
    Omission of Vincristine+Dexamethasone pulses
  • Drug: Inotuzumab Ozogamicin+Standard Maintenance Therapy
    Addition of IV Inotuzumab ozogamicin before Maintenance Therapy
    Other Name: Besponsa+Maintenance Therapy
  • Drug: Imatinib
    p.o. Imatinib
  • Drug: 6-tioguanine+Standard Maintenance Therapy
    Addition of p.o. 6-tioguanine to Standard Maintenance Therapy
  • Drug: Blinatumomab
    IV Blinatumomab
    Other Name: Blincyto
Study Arms  ICMJE
  • No Intervention: R1 - SR standard arm
    Standard risk arm receiving standard treatment (Delayed Intensification including Doxorubicin).
  • Experimental: R1 - SR experimental arm
    Standard risk arm, receiving Delayed Intensification without Doxorubicin IV 3 x 30 mg/m2/dose.
    Intervention: Drug: Omitted Doxorubicin
  • No Intervention: R2 - IR-low standard arm
    Standard treatment with Delayed Intensification including Doxorubicin and Maintenance including Vincristine+Dexamethasone pulses.
  • Experimental: R2 - IR-low experimental arm A
    Standard treatment with omission of Doxorubicin IV 3 x 30 mg/m2/dose in the Delayed Intensification phase.
    Intervention: Drug: Omitted Doxorubicin
  • No Intervention: R3 - IR-high standard arm
    Intermediate risk high arm receiving Standard Maintenance Therapy.
  • Experimental: R3-InO - IR-high experimental arm
    Inotuzumab IV 0,5 mg/m2, given on days 253, 260, 267 and on days 274, 281, 288 before start of Standard Maintenance Therapy.
    Intervention: Drug: Inotuzumab Ozogamicin+Standard Maintenance Therapy
  • Experimental: ABL-class fusions intervention
    Imatinib 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.
    Intervention: Drug: Imatinib
  • Experimental: R3-TEAM - IR-high experimental arm
    6-tioguanine p.o, 2,5-12,5 mg/m2, given daily in addition to Standard Maintenance Therapy.
    Intervention: Drug: 6-tioguanine+Standard Maintenance Therapy
  • Experimental: ALLTogether1 DS Blinatumomab intervention
    Blinatumomab IV, 5 mcg/m2/day up to 28 mcg/day (detailed dosing in protocol) continous infusion. Two 28 day courses with a two week treatment free interval in between. Blinatumomab courses replace Consolidation 1 and Consolidation 2 in the standard protocol adapted for Down syndrome patients.
    Intervention: Drug: Blinatumomab
  • Experimental: R2 - IR-low experimental arm B
    Standard treatment with omission of 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.
    Intervention: Drug: Omitted Vincristine+Dexamethasone pulses
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 12, 2020)
6430
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2032
Estimated Primary Completion Date June 30, 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year to 45 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Global Clinical Trial Manager ALLTogether1 +46 8 524 800 00 karin.flood@ki.se
Listed Location Countries  ICMJE Belgium,   Denmark,   Estonia,   Finland,   Germany,   Iceland,   Ireland,   Lithuania,   Netherlands,   Norway,   Portugal,   Sweden,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04307576
Other Study ID Numbers  ICMJE ALLTogether1
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Plan Description: The trial steering committee has not yet had the opportunity to discuss and decide on a plan to share IPD. Since no publication will be forthcoming from the study within at least 5 years (currently 2025), this shortcoming will be amended within a year (before 2021).
Responsible Party Mats Heyman, Karolinska University Hospital
Study Sponsor  ICMJE Mats Heyman
Collaborators  ICMJE
  • The Swedish Research Council
  • The Swedish Childhood Cancer Foundation
  • Pfizer
  • Servier
  • NordForsk
  • Aamu Pediatric Cancer Foundation
  • Gesellschaft fur Padiatrische Onkologie und Hamatologie - Germany
  • Clinical Trial Center North (CTC North GmbH & Co. KG)
  • Belgium Health Care Knowledge Centre
  • Karolinska Institutet
  • Cancer Research UK
  • Fundação Rui Osório de Castro
  • Acreditar - Associação de Pais e Amigos das Crianças com Cancro
  • Grupo Português De Leucemias Pediátricas
  • Amgen
  • Nova Laboratories Limited
  • Danish Child Cancer Foundation
  • Danish Cancer Society
  • The Novo Nordic Foundation
Investigators  ICMJE
Study Chair: Mats Heyman, MD, PhD Karolinska University Hospital
PRS Account Karolinska University Hospital
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP