Title: ALLTogether-1: A Treatment study protocol of the ALLTogether Consortium for children and young adults (1-45 years of age) with newly diagnosed acute lymphoblastic leukaemia (ALL)
Funder: Cancer Research UK

Abstract: Background The UK and 13 other countries have formed The ALLTogether Consortium in order to run this trial in childhood and young adult de-novo acute lymphoblastic leukaemia. Over 6000 patients will be recruited to the trial (nearly half of these from the UK). Whilst survivals for ALL are good, nearly 10% of children still die from the disease or its treatment. Chemotherapy for ALL is risk-stratified. Nevertheless, it still represents an under-treatment for some and a significant over-treatment for many with the associated toxicity that brings. Aims 1. To accurately risk-stratify patients into four risk groups so that therapeutic interventions can be accurately targeted. 2. To improve the chances of survival for the 10% of cases who will suffer relapse of their disease. B-cell precursor ALL patients with the highest risk of relapse will be selected for entry into parallel clinical trials of Chimeric Antigen Receptor T-cells. For the remaining B-cell patients with a high risk of relapse (60% of relapses are in this group), the randomised addition of a novel immunotherapeutic Inotuzumab Ozogamicin will be investigated. 3. To reduce treatment related toxicity by studying the randomised de-intensification of treatment for patients in the two lower-risk arms (the removal of anthracycline from the Delayed Intensification Block or pulses from maintenance chemotherapy). 4. To investigate whether the non-randomised addition of a Tyrosine Kinase Inhibitor to chemotherapy in patients with ABL-class mutations improves their outcome compared to historic controls. 5. To enable randomised studies of supportive care interventions designed to reduce the toxicity of treatment. 5. To enable the collection of an extensive, clinically annotated set of patient samples to enable further basic scientific research. Methods The trial will be open to all patients aged 1-24 with de novo ALL in the UK. They will be risk-stratified using clinical, genetic and response-based parameters into four risk groups. Patients in each risk group will be eligible to enter randomisations or interventions designed to answer the questions outlined above. Data will be collected centrally by the sponsor (Karolinska University Hospital, Sweden) and combined with data from the other participating countries for analysis. How the results will be used The data from the above questions will be used to determine the standard of care for future treatment of childhood and young adult ALL and in turn inform the development of the next generation of clinical trials.

Lay abstract: Background The UK and 13 other countries have formed The ALLTogether Consortium in order to run this trial in childhood and young adult de-novo acute lymphoblastic leukaemia. Over 6000 patients will be recruited to the trial (nearly half of these from the UK). Whilst survivals for ALL are good, nearly 10% of children still die from the disease or its treatment. Chemotherapy for ALL is risk-stratified. Nevertheless, it still represents an under-treatment for some and a significant over-treatment for many with the associated toxicity that brings. Aims 1. To accurately risk-stratify patients into four risk groups so that therapeutic interventions can be accurately targeted. 2. To improve the chances of survival for the 10% of cases who will suffer relapse of their disease. B-cell precursor ALL patients with the highest risk of relapse will be selected for entry into parallel clinical trials of Chimeric Antigen Receptor T-cells. For the remaining B-cell patients with a high risk of relapse (60% of relapses are in this group), the randomised addition of a novel immunotherapeutic Inotuzumab Ozogamicin will be investigated. 3. To reduce treatment related toxicity by studying the randomised de-intensification of treatment for patients in the two lower-risk arms (the removal of anthracycline from the Delayed Intensification Block or pulses from maintenance chemotherapy). 4. To investigate whether the non-randomised addition of a Tyrosine Kinase Inhibitor to chemotherapy in patients with ABL-class mutations improves their outcome compared to historic controls. 5. To enable randomised studies of supportive care interventions designed to reduce the toxicity of treatment. 5. To enable the collection of an extensive, clinically annotated set of patient samples to enable further basic scientific research. Methods The trial will be open to all patients aged 1-24 with de novo ALL in the UK. They will be risk-stratified using clinical, genetic and response-based parameters into four risk groups. Patients in each risk group will be eligible to enter randomisations or interventions designed to answer the questions outlined above. Data will be collected centrally by the sponsor (Karolinska University Hospital, Sweden) and combined with data from the other participating countries for analysis. How the results will be used The data from the above questions will be used to determine the standard of care for future treatment of childhood and young adult ALL and in turn inform the development of the next generation of clinical trials.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS