临床试验/2022-501050-11-01

2022-501050-11-01招募中3 期

ALLTogether1 - A Treatment Study Protocol of the ALLTogether Consortium for Children and Young Adults (0-45 Years of Age) with Newly Diagnosed Acute Lymphoblastic Leukaemia (ALL)

Karolinska University Hospital75 个研究点分布在 8 个国家目标入组 5,704 人开始时间: 2024年10月15日最近更新: 2025年6月27日

试验速览

阶段: 3 期
状态: 招募中
发起方
入组人数: 5,704
试验地点: 75
主要终点: 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.

研究概览入排标准结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

The primary objective of ALLTogether is to improve survival and quality of survival in infants, 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 either to obtain baseline information regarding characteristics, leukaemia-specific outcomes and toxicity or to be compared with well defined historical controls. A sub-group of patients will be identified that may benefit from novel immunotherapy.

研究设计

研究类型: Interventional

入排标准

年龄范围: 0 years 至 64 years（0-17 Years, 18-64 Years）
接受健康志愿者: 是

入选标准

•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.
•Age ≥ 0 days and < 46 years (one day before 46th birthday) at the time of diagnosis.
•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.
•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.

排除标准

•Age < 365 days at diagnosis and KMT2A-r BCP-ALL (documented presence of a KMT2A-split by FISH and/or a KMT2A transcript). These patients will be transferred to an appropriate trial for KMT2A-r BCP infant ALL if available.
•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, see section 18.
•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.
•Age >45 years at diagnosis (from the 46th birthday onwards)
•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 any patients with IG::MYC and a concurrent BCL2/6 rearrangement.
•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.
•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 germ-line mutation (index-cases) will remain in the study.
•Treatment with systemic corticosteroids (corresponding to >10mg prednisolone/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).

结局指标

主要结局

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 replacement of conventional chemotherapy for patients with Down syndrome and detectable MRD at the end of induction (ALLTogether1 DS) is the fraction of patients with undetectable MRD after one cycle of blinatumomab. This fraction will be compared with a well defined historic control cohort from the UKALL2011 protocol.

次要结局

Main study - The most important secondary outcome is overall survival (OS).
Main study - 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).
Main study - Over- and under-treatment will also be combined into resulting treatment-related mortality (TRM) and leukaemia specific mortality (LSM) rates.
Main study - 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.
Main study - 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 - Efficacy: - Overall survival (OS), - Cumulative incidence of relapse (ciR), - Cumulative incidence of Death in CR1 (ciDCR1), - Cumulative incidence of SMN (ciSMN), - Fraction of surviving patients treated with allogenic stem-cell transplant in second remission, - Cumulative incidence of HSCT in CR2
R1 and R2 - 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 if "possible"/"probable"/"proven" and agent (if isolated from sterile site/blood/BAL), -Rate of serious viral reactivation (EBV, VZV, HSV, CMV), mucositis with need for intravenous analgesic and/or nutritional support with parenteral nutrition, - The incidence of SAEs (except AESI)
Non-lethal toxicities for the DI-phase (R1 and R2): -The time-interval between the start of DI and the start of the next treatment- phase in days, - Rate of cardiac failure or serious arrhytmia (CTCAE ≥ grade 3).
Quantifiable measures of the toxicities listed above (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 4 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.
R3-InO and R3-TEAM secondary endpoints - Efficacy: -Overall survival (OS), - Cumulative incidence of relapse (ciR), -Occurence of CD22 negative relapse (InO), -Relation of all adverse outcomes with DNA-TG (TEAM).
R3-InO and R3-TEAM - 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)
Toxicity InO: -Incidence and severity of infections CTCAE grade > 3, -Incidence and duration of B-cell depletion reflected by immunoglobulin levels/IV immunoglobulin supplementation
Toxicity TEAM: -Cumulative incidence of SMN (ciSMN; TEAM), -Cumulative Incidence of NRH, -Cumulative Incidence of osteonecrosis, -Cumulative Incidence of hypoglycaemia
Exploratory endpoint (InO): CD22 expression level of leukemic cells in bone marrow samples at diagnosis and at TP2 (day 71).
ALLTogether1 DS secondary endpoints: -Event-Free Survival (EFS), -Overall Survival (OS), -Cumulative incidence of relapse (ciR) and CD19 negative relapse, -Cumulative incidence of Death in CR1 (ciDCR1), -Cumulative incidence of SMN (ciSMN), -Cumulative incidence of blinatumomab refractory disease, -Cumulative incidence of Protocol Therapy Failure
Exploratory endpoint ALLTogether1 DS: MRD response at any timepoint within 2 cycles of blinatumomab

研究者

发起方

Karolinska University Hospital

申办方类型

Hospital/Clinic/Other health care facility

责任方

Principal Investigator

主要研究者

Trial Central Office

Scientific

Karolinska University Hospital

研究点 (75)

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