Clinical trial NCT03911128: A Treatment Protocol for Participants 0-45 Years With Acute Lymphoblastic Leukaemia
Official title: A Treatment Study Protocol of the ALLTogether Consortium for Infants, Children and Young Adults (0-45 Years of Age) With Newly Diagnosed Acute Lymphoblastic Leukaemia (ALL): a Pilot Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Leukemia, Acute Lymphoblastic
Keywords: Leukemia
Acute Lymphoblastic
ALL
ALLTogether
Leukaemia
Lead sponsor: Karolinska University Hospital
Sponsor class: OTHER
Collaborators: name: Nordic Society for Pediatric Hematology and Oncology
name: The Swedish Childhood Cancer Foundation
name: NordForsk
First posted: 2019-04-10
Enrollment: 500
Sex: ALL
Minimum age (years): 0
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Participants 0-45 years with newly diagnosed acute lymphoblastic leukaemia. The protocol has no gender-bias. The total estimated recruitment in the pilot study is 500 participants.

Brief summary: The pilot study 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 platform 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 trials included in the study-design.

The pilot study is implemented as a master protocol without study specific interventions, thus as an observational study. The pilot study is for countries/study-groups who intend to join ALLTogether1 (including experimental interventions). For these countries the pilot study is crucial to optimise diagnostics, registration systems, collaborations with vendors, logistics and data-checks before starting the main study.

The study only includes "standard of care" treatment included in the master protocol.

Detailed description: The aims of the ALLTogether study are to improve survival and quality of survival for children and young adults with ALL. ALL in young people has excellent outcome with \>90% survival in children and about 75% in young adults. However, patients still die of disease - after relapse as a result of under-treatment.

Furthermore, a considerable fraction of younger patients are over-treated: All patients risk treatment-related death and some suffer long-term side-effects or secondary cancer. The rates of death from disease and death from therapy are almost the same for children. To show improvement with such good survival, large populations are needed.

Study groups from the five Nordic countries, Estonia and Lithuania (NOPHO), the UK (UKALL), the Netherlands (DCOG), Germany (COALL), Belgium (BSPHO), Ireland (PHOAI), Portugal (SHOP) and France (SFCE) have designed a common treatment protocol as new standard of care for children and young adults with ALL. The risk-stratification is based on a novel, personalised algorithm using clinical characteristics, genetic changes in the leukaemia and response to therapy.

The protocol will, based on a personalised risk-approach, define a platform for diagnosis and treatment onto which randomized as well as non-randomised interventions and translational studies can be added. This platform can also be used by countries joining the collaboration at a later date to prepare for full participation.

High-risk B-lineage patients may be stratified to Chimeric Antigen Receptor T-cell (CAR-T) therapy as an alternative to high-risk blocks and stem-cell transplant to reduce the side-effects.

Translational and other therapy-related research will be promoted by the common master protocol.

Eligibility criteria: 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 Haematopoietic 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-r BCP ALL (see exclusion criteria below).
* 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 and patients who intend to stay at least for the duration of the treatment 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.

Exclusion Criteria:

* Age \< 365 days and KMT2A-rearranged (KMT2A-r) BCP-ALL (documented presence of a KMT2A-split by FISH and/or a KMT2A fusion transcript). These patients will be transferred to an appropriate trial for infant KMT2A-r BCP-ALL, if available.
* 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::ABL1 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 (\>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, see section 17.8.
* Female patients, who are breast-feeding.
* Essential data missing from the registration of characteristics at diagnosis (in consultation with the protocol chair).

Primary outcomes:
measure: Event-free survival (EFS) compared to historical controls
timeFrame: 5 year
measure: Overall survival (OS) compared to historical controls
timeFrame: 5 year
Secondary outcomes:
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Aalborg University Hospital, Dept of Paediatrics
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Aarhus
country: Denmark
facility: Aarhus University Hospital, Child and Adolescent Health
city: Copenhagen
country: Denmark
facility: Rigshospitalet, Dept of Haematology
city: Copenhagen
country: Denmark
facility: Rigshospitalet, Dept of Paediatrics
city: Odense
country: Denmark
facility: Odense University Hospital, Dept of Paediatrics
city: Tallinn
country: Estonia
facility: North Estonia Medical Centre, Dept of Haematology
city: Tallinn
country: Estonia
facility: Tallinn Children´s Hospital, Dept of Paediatrics
city: Tartu
country: Estonia
facility: Tartu University Hospital
city: Helsinki
country: Finland
facility: Helsinki University Hospital, Dept of Haematology
city: Helsinki
country: Finland
facility: Helsinki University Hospital, Dept of Paediatrics
city: Kuopio
country: Finland
facility: Kuopio University Hospital, Dept of Haematology
city: Kuopio
country: Finland
facility: Kuopio University Hospital, Dept of Paediatrics
city: Oulu
country: Finland
facility: Oulu University Hospital, Dept of Haematology, Dept of Medicine
city: Oulu
country: Finland
facility: Oulu University Hospital, Dept of Paediatrics
city: Tampere
country: Finland
facility: Tampere University Hospital, Dept of Haematology
city: Tampere
country: Finland
facility: Tampere University Hospital, Dept of Paediatrics
city: Turku
country: Finland
facility: Turku University Hospital, Clinical Haematology and Stem Cell Transplantation Unit
city: Turku
country: Finland
facility: Turku University Hospital, Dept of Paediatrics
city: Reykjavík
country: Iceland
facility: Landspitali University Hospital, Children's Hospital
city: Vilnius
country: Lithuania
facility: Children's Hospital, Affiliate of Vilnius University Hospital
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital
city: Bergen
country: Norway
facility: Haukeland University Hospital, Dept of Haematology
city: Bergen
country: Norway
facility: Haukeland University Hospital, Dept of Paediatrics
city: Oslo
country: Norway
facility: Oslo University Hospital, Dept of Haematology
city: Oslo
country: Norway
facility: Oslo University Hospital, Dept of paediatric haemato- and oncology
city: Stavanger
country: Norway
facility: Stavanger University Hospital, Dept of Haematology
city: Tromsø
country: Norway
facility: University Hospital North Norway, Dept of Haematology
city: Tromsø
country: Norway
facility: University Hospital of North Norway, Dept of Paediatrics
city: Trondheim
country: Norway
facility: St. Olavs University Hospital, Dept of Paediatrics
city: Trondheim
country: Norway
facility: St. Olavs University Hospital, Dept of Haematology
city: Barcelona
country: Spain
facility: Hospital Universitario San Joan de Déu
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Nino Jesus
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital, Section for Haematology and coagulation
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital, Dept of Paediatric Haematology and Oncology
city: Linköping
country: Sweden
facility: Linköping University Hospital, Dept of Haematology
city: Linköping
country: Sweden
facility: Linköping University Hospital, Dept of Paediatrics
city: Lund
country: Sweden
facility: Skåne University Hospital, Dept of Haematology
city: Lund
country: Sweden
facility: Skåne University Hospital, Dept of Paediatrics
city: Stockholm
country: Sweden
facility: Karolinska University Hospital, Dept of Paediatric Oncology and Haematology
city: Stockholm
country: Sweden
facility: Karolinska University Hospital, Patient area Haematology
city: Umeå
country: Sweden
facility: Norrland University Hospital, Dept of Haematology
city: Umeå
country: Sweden
facility: Norrland University Hospital, Dept of Paediatrics
city: Uppsala
country: Sweden
facility: Uppsala University Hospital, Dept of Haematology
city: Uppsala
country: Sweden
facility: Uppsala University Hospital, Dept of Paediatric Haematology and Oncology
city: Örebro
country: Sweden
facility: Örebro University Hospital, Section for Haematology
Study officials:
affiliation: Karolinska University Hospital
name: Mats Heyman, M.D. PhD
role: STUDY_CHAIR
References:
citation: Toft N, Birgens H, Abrahamsson J, Griskevicius L, Hallbook H, Heyman M, Klausen TW, Jonsson OG, Palk K, Pruunsild K, Quist-Paulsen P, Vaitkeviciene G, Vettenranta K, Asberg A, Frandsen TL, Marquart HV, Madsen HO, Noren-Nystrom U, Schmiegelow K. Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia. Leukemia. 2018 Mar;32(3):606-615. doi: 10.1038/leu.2017.265. Epub 2017 Aug 18.
citation: Schramm F, Zimmermann M, Jorch N, Pekrun A, Borkhardt A, Imschweiler T, Christiansen H, Faber J, Feuchtinger T, Schmid I, Beron G, Horstmann MA, Escherich G. Daunorubicin during delayed intensification decreases the incidence of infectious complications - a randomized comparison in trial CoALL 08-09. Leuk Lymphoma. 2019 Jan;60(1):60-68. doi: 10.1080/10428194.2018.1473575. Epub 2018 Jul 3.
citation: Mondelaers V, Suciu S, De Moerloose B, Ferster A, Mazingue F, Plat G, Yakouben K, Uyttebroeck A, Lutz P, Costa V, Sirvent N, Plouvier E, Munzer M, Poiree M, Minckes O, Millot F, Plantaz D, Maes P, Hoyoux C, Cave H, Rohrlich P, Bertrand Y, Benoit Y; Children-s Leukemia Group (CLG) of the European Organization for Research and Treatment of Cancer (EORTC). Prolonged versus standard native E. coli asparaginase therapy in childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma: final results of the EORTC-CLG randomized phase III trial 58951. Haematologica. 2017 Oct;102(10):1727-1738. doi: 10.3324/haematol.2017.165845. Epub 2017 Jul 27.
citation: Vora A, Goulden N, Wade R, Mitchell C, Hancock J, Hough R, Rowntree C, Richards S. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2013 Mar;14(3):199-209. doi: 10.1016/S1470-2045(12)70600-9. Epub 2013 Feb 7.
citation: Pieters R, de Groot-Kruseman H, Van der Velden V, Fiocco M, van den Berg H, de Bont E, Egeler RM, Hoogerbrugge P, Kaspers G, Van der Schoot E, De Haas V, Van Dongen J. Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group. J Clin Oncol. 2016 Aug 1;34(22):2591-601. doi: 10.1200/JCO.2015.64.6364. Epub 2016 Jun 6.