| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute lymphoblastic leukaemia (ALL) |
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| E.1.1.1 | Medical condition in easily understood language |
| Blood cancer in children and young adults |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000844 |
| E.1.2 | Term | Acute lymphoblastic leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of ALLTogether is to improve survival and quality of survival in children and young adults with acute lymphoblastic leukaemia by a number of interventions that will be tested in a randomised fashion, compared with well-defined control-populations within the Protocol or explored in a non-randomised fashion to obtain baseline information regarding characteristics, leukaemia-specific outcomes and toxicity. A sub-group of patients will be identified that may benefit from novel immunotherapy. |
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| E.2.2 | Secondary objectives of the trial |
•To investigate if patients in the de-intensification (SR- & IR-low) randomisations derived any benefit from this de-intensification. Overall survival(OS) and leukaemia-specific adverse outcomes are balanced against secondary measures of toxicity, partly taking into account the toxicity of relapse treatment. Quality of life(QoL) will also be measured to ascertain and compare the burden of therapy.
•To ascertain if addition of Inotuzumab(InO) impacts OS or other leukaemic adverse outcomes and to assess if the toxicity induced by InO is significant & acceptable. QoL will also be measured to assess the burden of therapy including the experimental intensification.
•For patients treated with TKI, baseline data regarding OS, specific leukaemic outcomes, toxicity and QoL will be collected for future comparisons.
•For patients defined as eligible for CAR-T survival, specific leukaemic adverse events, toxicity & QoL resulting from conventional HR-therapy & CAR-T cell treatment is measured. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
•CSF-FLOW sub-study protocol, v 1.0 05Aug2019. Related objectives:
-To use CSF FCM to improve diagnostic tests for CNS leukaemia compared to conventional CSF cytology and to develop a recommended protocol for CSF flow cytometry with external quality assessment to ensure uniformity of measurement
-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
-To investigate whether positive FCM can identify children at increased risk of CNS relapse (FCM positive at day 15 onwards) might benefit from escalated CNS-directed therapy or a switch to more intensive treatment arms
-To collect matching CSF supernatant for studies comparing CSF FCM with soluble biomarkers (e.g. metabolic, cell-free DNA, proteomic and microRNA)
•Efficacy of Imatinib in ABL-class fusion positive ALL, v 1.0 05Aug2019. Related Objectives:
-To determine the efficacy of imatinib in the treatment of ABL-class leukemia
-To find the best biomarkers for TKI response in ABL-class ALL
-To determine the frequency of intrinsic (at diagnosis) and acquired TKI resistance (due to treatment)
-To find causes of TKI resistance in ABL-class patients
-To determine the percent of ABL-class patients who need to switch from IR-high to HR because of high MRD levels
-To determine the effect of imatinib exposure on clinical outcome
-To determine the molecular response to imatinib by monitoring fusion transcript levels and mutational spectrum at diagnosis and during follow-up
-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
-To determine the phosphorylation status of ABL-class proteins and presence of TKI-resistance associated mutations in ABL genes prior to and following imatinib treatment
-To determine the presence of mutations in regulatory /other genes before and during imatinib treatment and address the importance of these mutations in TKI resistance
-To determine whether the efficacy of TKIs depends on the type of fusion gene
•Biomarkers to Reform Approaches to therapy-Induced Neurotoxicity (BRAIN) sub-study, v. 1.0 05Aug2019. Related objectives:
-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
-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
•A2G maintenance therapy pharmacokinetics/-dynamics sub-study, v 1.0 05Aug2019. Related objectives:
-To map pharmacokinetics of 6MP and MTX during maintenance therapy in all patients in the A2G protocol
-To associate metabolite profiles with TPMT and NUDT15 variants, as routinely analysed in A2G
-To explore within the association of event-free survival with DNA-TG and other 6MP/MTX metabolites
-To explore the association between risk of second cancers with DNA-TG and other 6MP/MTX metabolites
-To explore the association of risk of invasive infections with DNA-TG and other 6MP/MTX metabolites
-To explore the association of risk of osteonecrosis with DNA-TG and other 6MP/MTX metabolites
-To explore the association of sinusoidal obstruction syndrome with DNA-TG and other 6MP/MTX metabolites
•Association between asparaginase activity levels and outcome, v 1.0 05Aug2019. Related objectives:
-To study the association between asparaginase activity levels and outcome ( MRD, relapse, survival)
-To evaluate the association between asparaginase activity levels and toxicities, such as pancreatitis, infections and deep venous thrombosis (DVT)
-To evaluate the association between asparaginase activity levels and hepatotoxicity
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| E.3 | Principal inclusion criteria |
1. Patients newly diagnosed with T-lymphoblastic (T-cell) or B-lymphoblastic precursor (BCP) leukaemia (ALL) according to the WHO-classification of Tumours of Haematopetic 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.
2. Age ≥ 365 days and < 46 years (one day before 46th birthday) at the time of diagnosis.
3. 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 ).
4. The ALL diagnosis should be confirmed by an accredited laboratory at a participating paediatric oncology or adult haematology centre.
5. The patient should be diagnosed and treated at a participating paediatric oncology or adult haematology centre in the participating countries.
6. 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.
7. All women of childbearing potential (WOCBP) have to have a negative pregnancy test within 2 weeks prior to the start of treatment.
8. For each intervention/randomisation an additional set of inclusion-criteria is provided. |
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| E.4 | Principal exclusion criteria |
1. Age < 365 days at diagnosis (infant ALL) or >45 years at diagnosis.
3. Patients with a previous malignant diagnosis (ALL as a second malignant neoplasm - SMN).
4. Relapse of ALL.
5. 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).
6. 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.
7. ALL prone syndromes (e.g. Li-Fraumeni syndrome, germline ETV6 mutation), except for Down syndrome. Exploration for such ALL prone syndromes is not mandatory.
8. 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).
9. Pre-existing contraindications to any treatment according to the ALLTogether protocol (constitutional or acquired disease prior to the diagnosis of ALL preventing adequate treatment).
10. 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.
11. Women of childbearing potential who are pregnant at the time of diagnosis.
12. 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, see section 17.7.
13. Female patients, who are breast-feeding.
14. Essential data missing from the registration of characteristics at diagnosis (in consultation with the protocol chair).
15. For each intervention/randomisation an additional set of exclusion-criteria is provided. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- 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.
- The primary endpoint for the randomised interventions is disease-free survival (DFS) – as defined in the protocol.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| EFS/DFS: 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). |
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| E.5.2 | Secondary end point(s) |
Main study secondary end-points
The most important secondary outcome is overall survival (OS).
Additional secondary measures of antileukaemic efficacy are: rate of -death during induction, -resistant disease, cumulative incidence of: -relapse (ciR), -death in first complete remission (ciDCR1) and -second malignancy (ciSMN).
Over- and under-treatment events will also be combined into resulting treatment-related mortality (TRM) and leukaemia specific mortality (LSM) rates.
Since over-treatment also includes cured patients who suffer potentially permanent side-effects, data will be collected regarding the incidence of some adverse events of special interest.
De-escalation of therapy may also result in relapses that have to be rescued with allogeneic stem-cell transplant (allo-SCT), which is associated with serious permanent side effects. Therefore, the incidence of allo-HSCT in CR1 and CR2 will also be measured.
An important aspect of evaluation of the quality of survival is measurement of quality of life (QoL). The whole protocol, as well as each of the non-randomised and randomised interventions will also be evaluated by measurements of quality of life (QoL). QoL will be measured by EQ5D-based instruments before and after all the randomised phases in all randomisations as well as later in the therapy and after cessation of treatment.
R1 and R2 secondary end-points
Efficacy:
• Overall survival (OS)
• The components of the primary end-point - DFS (ciR, ciDCR1 and ciSMN) are relevant secondary end-points since they are likely to work in opposite directions in a de-escalation setting
• Fraction of surviving patients treated with allogeneic stem-cell transplant in second remission and cumulative incidence of HSCT in CR2 will also be measured
Toxicity:
The studies are powered to answer the primary end-point non-inferiority question with a certain safety-margin. Even if reduction of exposure to potentially toxic therapy is an objective in itself, it is also reasonable to show some immediately measurable benefit from the reduction of therapy if the study is successful and non-inferiority can be shown.
Non-lethal toxicities for the DI-phase (R1 and R2):
• Rate of febrile neutropenia (yes/no) and agent (if isolated from a sterile site/blood)
• Rate of invasive fungal infection (yes/no) together with assessment of “possible”/"probable”/”proven” and agent (if isolated from sterile site/blood/BAL)
• Rate of serious viral reactivation (EBV, VZV, HSV and CMV), mucositis with need for intravenous analgesics and/or nutritional support with parenteral nutrition
• The incidence of SAEs (except AESI)
• The time-interval between the start of DI and the start of the next treatment- phase in days.
• Rate of cardiac failure or serious arrhythmia (CTCAE ≥ grade 3)
In addition the following quantifiable measures of the toxicities listed above will be measured at the same time-points:
• days admitted to hospital during the randomised phase and until the
start of the next treatment phase
• days on iv antibiotics
• days on advanced antifungals
• days on iv analgesics and/or nutritional support with parenteral nutrition
Non-lethal toxicity for the Maintenance-phase (R2)
Measured at the beginning of Maintenance and every 3 months during the maintenance-phase:
• Rate of VCR-neuropathy Grade ≥3 according to the PdL definition
• The number of doses of VCR that had to be reduced or omitted
• Cumulative incidence of symptomatic osteonecrosis + grade.
Follow-up end-point of obesity
Body-mass index at the time of cessation of therapy and 5 years after the end of therapy.
Secondary end-points R3-InO
Efficacy:
• Overall survival (OS)
• Cumulative incidence of relapse (CIR)
• Occurrence of CD22 negative relapse
Toxicity:
• Incidence and severity of SOS/VOD all grades
• Incidence and severity of other liver toxicity (defined as AST/ALT elevations grade > 3 and bilirubin grade > 3)
• Incidence and severity of infections CTCAE grade > 3
• Incidence and duration of B-cell depletion reflected by immunoglobulin levels/IV immunoglobulin supplementation
Exploratory end-point:
CD22 expression level of leukemic cells in bone marrow samples at diagnosis and at TP2 (day 71). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All efficacy-measures will be ascertained as 5-year estimates.
Incidence, rates and frequencies of the toxicity end-points will be assessed at the end of therapy for all toxicities except obesity in R2, which is assessed finally 5 years after cessation of therapy.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 7 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 108 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| Last visit of the last subject |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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