This study has been transitioned to CTIS with ID 2022-501050-11-01 check the CTIS register for the current data. The primary objective of ALLTogether is to improve survival and quality of survival in children and young adults with acute…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- 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.
- The primary endpoint for the DS study is fraction of MRD undetectable
patients (*Complete MRD response*) at the end of one cycle of Blinatumomab
Secondary outcome
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
• Body-mass index at the time of cessation of therapy and 5 years after the end
of therapy.
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.
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).
Secondary end-points DS:
• Overall survival
• Incidence of relapse
• Incidence of Death in Complete Remission
• Incidence of second malignancies
• Incidence of CD19 negative relapse
• Event Free Survival
• Incidence of Blinatumomab refractory disease
• Incidence of Protocol Therapy Failure
Background summary
Acute Lymphoblastic Leukaemia (ALL) is the most common form of childhood
malignancy, with an incidence that varies between approximately 100 children
per year in the Netherlands. The incidence in adults is approximately a third
of that in children, indicating that the disease is relatively much more common
among children when the limited time-span of childhood is taken into account.
Treatment results have improved over time due to risk-adapted therapy developed
by cooperative groups.
In the discussions leading up to the formation of the consortium,
representatives from the study-groups identified four major problem areas that
should be addressed. The problem areas identified are:
1) The cure of the remaining <10% of children and 20-30% of adults that still
die of ALL:
The prognosis for children and young adults with ALL has improved dramatically
in the last 40-50 years. Currently, overall survival exceeds 90% for children
and 70-80% for young adults. The identification of clinical and genetic
risk-factors and increasingly sophisticated means of measuring early response
to therapy by minimal residual disease (MRD) have refined the
risk-stratification and improved risk-adapted treatment protocols. This
intensification has had several effects apart from the generally improved
outcome:
- truly resistant disease, not responding to any therapeutic measures has
become very rare in ALL in children and young adults treated according to
contemporary protocols;
- further general intensification of therapy is not likely to improve the
outcome, since the reduction in relapses means that, despite best possible
care, an increasing fraction of adverse events are the result of
treatment-related causes - death in first complete remission (DCR1) and second
malignant neoplasm (SMN)
2) Over-treatment:
When treatment-results are compared over a longer time-period, considered in
the context of the therapy given at that time and the successive
intensification of therapy generally, it is obvious that a substantial fraction
of all patients are over-treated with contemporary treatment protocols.
The over-treatment has several serious consequences:
- one of the limiting factors for further intensification is the likely rise in
treatment-related mortality, which is currently 3-5% of all paediatric patients,
but higher for young adults; Treatment related mortality is particularly high
in Down Syndrome with an incidence of between 10-20 %
- the consequences of acute and chronic toxicity is a fraction of longterm
survivors that suffer from serious long-term consequences, which may limit
their remaining expected life-span and impair their quality of life as a result
of the therapy;
- the protracted standard therapy imposes unnecessary burdens on the patients
and their families with consequences for schooling, work and social life.
3) The identification of new biological sub-groups with potential new targets
for therapy.
4) Lacking statistical power with improving results
Study objective
This study has been transitioned to CTIS with ID 2022-501050-11-01 check the CTIS register for the current data.
The primary objective of ALLTogether is to improve survival and quality of
survival in children and young adults with acute lymphoblastic leukaemia
Study design
The ALLTogether treatment protocol is an international multi-centre
prospective, open label study with several (phase III) randomised parts. The
backbone of the protocol is the basis of a platform onto which several
randomisations and other interventions can be added
Intervention
- R1: omission of Doxorubicin in the delayed intensification phase of the SR
treatment
- R2: omission of Doxorubicin in the delayed intensification phase or
Vincristine-Dexamethasone pulses in maintenance phase of the IR-low treatment
- R3: addition of Inotuzumab Ozogamicin (InO) or 6-Tiolguanine to the
maintenance phase of the IR-high treatment
- Addition of Imatinib to the treatment of patients with ABL-class fusion
positive ALL; collection of additional bonemarrow and blood at standard
sampling timepoints
- Replacement of 2 consolidation cycles with 2 cycles of Blinatumomab in IR/HR
patients with Down Syndrome
- Quality of Life questionnaires
- Asparaginase peak levels study: additional blood sampling at standard
sampling timepoints
- CSF-FLOW study: additional CSF fluid sampling at standard sampling timepoints
- MRD study: collection of additional Bonemarrow at the end of the
Consolidation phase, at standard sampling timepoint
- Maintenance, TDM MTX/6MP: additional blood sampling during Maintenance every
1-3 months, at standard sampling timepoints.
- BRAIN study: play some computer games after end of treatment.
Study burden and risks
The ALLTogether1 treatment protocol is a developed by a consortium of study
groups from 14 different European countries. Treatment according to this
protocol is the standard treatment for children and young adults with ALL in
these European countries. In the Netherlands all patients until 18 years of age
will be treated according to this protocol in the Princess Máxima Center. Young
adults from 19 until 25 years of age will be treated according to this
protocol in the UMC Utrecht.
Most important risks are standard in a (pediatric) oncology treatment. There
are no additional risks for the extra blood/bonemarrow/CSF fluid samplings at
the standard sampling timepoints. Extra bloodsamples are taken from the PAC at
times that this is already in use for a standard blood sampling.
In R1 and R2 there is a potential additional risk due to deintensification of
therapy.
In R3 the possible additional risks are mainly the side effects of inotuzumab
ozogamicin or 6-tioguanin, including currently unknown side effects. See also
the InO subprotocol (ch. 13-Structured Risk Analysis), and the TEAM subprotocol.
In the TKI study the possible additional risks are mainly the side effects of
Imatinib.
In the DS study the possible additional risks are mainly the side effects of
Blinatumomab.
Tomtebodavägen 18 A
Stockholm 17177
SE
Tomtebodavägen 18 A
Stockholm 17177
SE
Listed location countries
Age
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 > 0 days and < 46 years (one day before 46th birthday) at the time of
diagnosis.
3. Patients with surface IG negative BCP-ALL and an IG::MYC rearrangement
unless they have a concurrent BCL2/6 rearrangement. T-ALL patients with MYC
translocations.
4. Informed consent signed by the patient and/or parents/legal guardians
according to country-specific age-related guidelines.
5. The ALL diagnosis should be confirmed by an accredited laboratory at a
participating paediatric oncology or adult haematology centre.
6. The patient should be diagnosed and treated at a participating paediatric
oncology or adult haematology centre in the participating countries.
7. 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.
8. 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
1. Age < 365 days at diagnosis and KMT2A-rearranged (KMT2A-r) BCP ALL
(documented presence of a KMT2A-split by FISH and/or a KMT2A transcript). These
patients will be transfered to an appropriate trial for KMT2A-r BCP infant ALL
if available.
2. Age > 45 years at diagnosis (from the 46th birthday onwards).
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)(q24;q32), t(2;8)(p12;q24),
t(8;22)(q24;q11) translocations involving the MYC gene and breakpoint as in
mature B-NHL/ALL) or any patients with IG::MYC and a concurrent BCL2/6
rearrangement.
6. Patients with Ph-positive ALL (documented presence of t(9;22)(q34;q11)
and/or of the BCR::ABL1 fusion transcript). These patients will be transferred
to an adequate trial for t(9;22) if available.
7. Previously known ALL prone syndromes (e.g. Li-Fraumeni syndrome, germline
ETV6 mutation), except for Down syndrome. Exploration for such ALL prone
syndromes is not mandatory and patients in whom genetic work-up reveals a new
germline mutation (index-cases) will remain in the study.
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).
For each intervention/randomisation an additional set of exclusion-criteria is
provided.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2022-501050-11-01 |
| EudraCT | EUCTR2018-001795-38-NL |
| ClinicalTrials.gov | NCT04307576 |
| CCMO | NL71370.041.19 |