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)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 6,430
- 试验地点
- 267
- 主要终点
- Event-free survival (EFS) for the whole protocol
研究概览
简要总结
ALLTogether collects the experience of previously successful treatment of infants, 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.
详细描述
ALLTogether is a European clinical treatment study for acute lymphoblastic leukaemia (ALL) in infants, children and young adults. The aims are to improve survival and quality of survival. In young people, ALL has excellent outcome with an overall survival of about 92% in children and 75% in young adults. Infants with BCP-ALL and KMT2A-rearrangements have a worse outcome and are treated according to separate protocols, but infants with KMT2A-germline and T-cell ALL have acceptable outcome on standard ALL therapy. 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.
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 infants, 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 0 Years 至 45 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
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 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 0 - < 46 years (one day before 46th birthday) at the time of diagnosis with the exception of infants with KMT2A-rearranged (KMT2A-r) BCP ALL.
- •Patients with surface immunoglobulin negative (sIG-) 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.
- •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 and KMT2A-rearranged (KMT2A-r) BCP-ALL (documented presence of a KMT2A-split by FISH and/or a KMT2A fusion transcript).
- •Age >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 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::ABL fusion transcript). These patients will be transferred to an appropriate 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).
- •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.
研究组 & 干预措施
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.
干预措施: Inotuzumab Ozogamicin+Standard Maintenance Therapy (Drug)
R3-TEAM - IR-high experimental arm
6-tioguanine p.o, 2,5-12,5 mg/m2, given daily in addition to Standard Maintenance Therapy.
干预措施: 6-tioguanine+Standard Maintenance Therapy (Drug)
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.
干预措施: Omitted Vincristine+Dexamethasone pulses (Drug)
R1 - SR standard arm
Standard risk arm receiving standard treatment (Delayed Intensification including Doxorubicin).
R2 - IR-low standard arm
Standard treatment with Delayed Intensification including Doxorubicin and Maintenance including Vincristine+Dexamethasone pulses.
R3 - IR-high standard arm
Intermediate risk high arm receiving Standard Maintenance Therapy.
R1 - SR experimental arm
Standard risk arm, receiving Delayed Intensification without Doxorubicin IV 3 x 30 mg/m2/dose.
干预措施: Omitted Doxorubicin (Drug)
R2 - IR-low experimental arm A
Standard treatment with omission of Doxorubicin IV 3 x 30 mg/m2/dose in the Delayed Intensification phase.
干预措施: Omitted Doxorubicin (Drug)
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.
干预措施: Imatinib (Drug)
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.
干预措施: Blinatumomab (Drug)
结局指标
主要结局
Event-free survival (EFS) for the whole protocol
时间窗: 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.
Disease-free survival (DFS) R1 + R2
时间窗: 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
MRD response after 1 cycle of Blinatumomab
时间窗: 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)
Event-free survival (EFS) for the TKI intervention
时间窗: 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) R3
时间窗: 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).
次要结局
- Induction death(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))
- Overall survival (OS) for R3(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up)
- Overall survival (OS) for ALLTogether1 DS(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.)
- Cumulative incidence of CD19 negative relapse for ALLTogether1 DS(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up)
- Cumulative incidence of second malignancy for ALLTogether1 DS(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.)
- Overall survival (OS) for the whole protocol(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.)
- Overall survival (OS) for R3-TEAM associated with DNA-TG(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up)
- Cumulative incidence relapse for R3(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 malignant neoplasm (SMN) for the whole protocol(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.)
- Cumulative incidence of second malignancy for R1+R2(5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.)
- Cumulative incidence of second malignancy for R3-TEAM in association with DNA-TG(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up.)
- Overall survival (OS) for R1 + R2(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 (OS) for TKI(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up (TKI).)
- Resistant disease(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))
- Cumulative incidence of relapse for the whole protocol(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.)
- Cumulative incidence of second malignancy for TKI(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.)
- Cumulative incidence of relapse for R1 + R2(5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.)
- Cumulative incidence relapse for R3-TEAM in association with DNA-TG(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up)
- Cumulative incidence CD22 negative relapse for R3(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up)
- Cumulative incidence relapse for TKI(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up)
- Cumulative incidence of second malignancy for R3(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 death in complete remission for R1+R2(5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up.)
- Cumulative incidence of death in complete remission for TKI(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up)
- Cumulative incidence of death in complete remission for ALLTogether1 DS(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up)
- Cumulative incidence of treatment-related mortality R3(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up)
- Cumulative incidence relapse for ALLTogether1 DS(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up)
- Cumulative incidence of death in complete remission for the whole protocol(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.)
- Leukaemia specific mortality for R1+R2(5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.)
- Incidence of Adverse Events of Special Interest (AESIs) extra assessment (R1+R2)(Cumulative incidence of AESIs estimated 3 months after start of maintenance (R1+R2) and at the end of maintenance (R2))
- Cumulative incidence of Sinusoidal Obstruction Syndrome (SOS) and Nodular Regenerative Hyperplasia (NRH) for R3-TEAM(Cumulative incidence of SOS/NRH estimated at the end of follow-up.)
- Cumulative incidence of death in complete remission for R3(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 treatment-related mortality R1+R2(5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up.)
- Leukaemia specific mortality for the whole protocol(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.)
- Incidence of Adverse Events of Special Interest (AESIs) extra assessment (R3)(Cumulative incidence of AESIs estimated at the end of maintenance.)
- Cumulative incidence of Osteonecrosis for R3-TEAM(Cumulative incidence of osteonecrosis estimated at the end of follow-up.)
- Cumulative incidence of treatment-related mortality for the whole protocol(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.)
- Cumulative incidence of treatment-related mortality TKI(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up)
- Leukaemia specific mortality for R3(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up)
- Incidence of Serious Adverse Events (SAEs) and Adverse Events (AEs) related to R3(From time of randomisation until the end of maintenance therapy (approximately 77 weeks from randomisation))
- Incidence of Blinatumomab refractory disease for ALLTogether1 DS(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))
- Leukaemia specific mortality for TKI(5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up)
- Incidence of Adverse Events of Special Interest (AESIs) per treatment-phase in the whole protocol and TKI intervention(From time of diagnosis after each treatment-phase (one extra in the middle of maintenance) and annually until 5 years from discontinuation of therapy.)
- Quantitative measures of toxicity R1+R2(From time of randomisation, assessment after delayed intensification and 6 weeks after start of maintenance)
- Metabolic consequences of steroid exposure (R2)(At the end of therapy (approximately 94 weeks from randomisation) and 5 years after discontinuation of treatment)
- Association of Disease-free survival (DFS) with DNA-TG for R3-TEAM(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)
- Event-free survival (EFS) for ALLTogether1 DS(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.)
- Incidence of Protocol Therapy Failure for ALLTogether1 DS(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))
研究者
Mats Heyman
MD, Associate Professor
Karolinska University Hospital