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)

The primary objective of the ALLTogether1 study is to enhance **survival** and quality of survival in infants, children, and young adults diagnosed with **Acute Lymphoblastic Leukaemia** (ALL). This will be achieved through various interventions tested in a randomized manner, compared with well-defined control populations within the protocol. Additionally, some interventions will be explored non-randomly to gather baseline data on characteristics, leukaemia-specific outcomes, and toxicity, or to compare with historical controls. Identifying a subgroup of patients who may benefit from novel immunotherapy is also a key focus. This objective is clinically relevant as it aims to improve treatment outcomes and reduce the burden of ALL, a critical concern in pediatric oncology.

Secondary objectives include:

• Investigating if patients with low SR and IR can benefit from therapy de-intensification, balancing overall survival and leukaemia outcomes against toxicity, including relapse treatment, and assessing the quality of life (QoL) to compare therapy burdens.
• Determining if the addition of Inotuzumab or low-dose 6-thioguanine impacts overall survival or other adverse outcomes, and evaluating the significance and acceptability of the induced toxicity, with QoL measurements assessing the burden of experimental intensifications.
• Collecting baseline data on overall survival, adverse outcomes, toxicity, and QoL for patients treated with TKI for future reference.
• Assessing if replacing conventional chemotherapy with blinatumomab can improve leukaemic outcomes and reduce toxicity in patients with Down syndrome.
• Measuring survival, specific leukaemic adverse events, toxicity, and QoL in patients eligible for CAR-T therapy, resulting from conventional high-risk therapy and CAR-T cell treatment.

The clinical trial involves a total of **2090 participants** diagnosed with **Acute Lymphoblastic Leukaemia** (ALL). The study population includes infants, children, and young adults aged from birth up to just before their 46th birthday. Both **male and female** subjects are included, and the trial specifically targets a vulnerable population. Participants were selected based on a confirmed diagnosis of T-lymphoblastic or B-lymphoblastic precursor leukaemia, as per the WHO classification, with diagnosis confirmed by an accredited laboratory at a participating paediatric oncology or adult haematology centre. The trial does not specify particular lifestyle considerations such as diet or physical activity. However, it is noted that all women of childbearing potential must have a negative pregnancy test prior to the start of treatment. The trial is conducted in participating countries, and participants must be residents or intend to settle in these countries. The study aims to improve survival and quality of survival through various interventions, including novel immunotherapy for a sub-group of patients.

The clinical trial is designed to evaluate the efficacy and safety of various interventions in patients with **Acute Lymphoblastic Leukaemia** (ALL). This is a **randomized, double-blind, controlled** trial with a primary objective to improve survival and quality of life in infants, children, and young adults diagnosed with ALL. The trial will compare new interventions against well-defined control populations or historical controls. The trial is expected to run from June 2020 to June 2030, with participant involvement lasting up to 106 weeks, depending on the treatment arm.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and residency. Following the screening, participants will be randomized into different treatment arms. The trial includes multiple follow-up visits to monitor treatment efficacy and safety, assess disease progression, and collect data on quality of life. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it in the participant's best interest. The trial will measure primary endpoints such as event-free survival and disease-free survival, alongside secondary endpoints including overall survival, relapse rates, and quality of life assessments. The study will also evaluate the incidence of treatment-related toxicities and adverse events.

The clinical trial involves the administration of **TIOGUANINE**, an oral suspension formulated for pediatric use. The active substance, tioguanine, is of chemical origin. The maximum daily dose is 12.5 mg/m², with a total maximum dose of 6212.5 mg/m² over a treatment period of 71 days. The route of administration is oral, and participant compliance will be monitored throughout the trial.

**HYDROCORTISONE SODIUM SUCCINATE** is utilized as a non-experimental treatment in the form of a powder for solution for injection or infusion. The active substance is chemically derived, with a maximum daily dose of 24 mg and a total dose of 144 mg over a 6-day period. The administration route is intrathecal.

**MERCAPTOPURINE** is administered in both oral suspension and tablet forms. The chemical origin substance is dosed at a maximum of 75 mg/m² daily, with a total dose of 37275 mg/m² over 71 days. The route of administration is oral.

**BLINATUMOMAB**, marketed as BLINCYTO, is provided as a powder for concentrate and solution for infusion. This protein-based treatment is administered intravenously, with a maximum daily dose of 28 µg and a total dose of 1568 µg over 8 days.

**VINCRISTINE SULFATE** is available as a solution for injection, with a chemical origin. The maximum daily dose is 1.5 mg/m², and the total dose is 27 mg/m² over 18 days. The administration route is intravenous.

**DOXORUBICIN** is administered as a solution for injection, with a maximum daily dose of 30 mg/m² and a total dose of 90 mg/m² over 3 days. The chemical origin substance is delivered intravenously.

**DEXAMETHASONE** is provided in tablet form, with a maximum daily dose of 6 mg/m² and a total dose of 540 mg/m² over 90 days. The chemical origin substance is administered orally.

**METHOTREXATE** is used in both solution for injection and tablet forms. The chemical origin substance is administered intrathecally with a maximum daily dose of 12 mg and a total dose of 72 mg over 6 days, or orally with a maximum daily dose of 20 mg/m² and a total dose of 9940 mg/m² over 71 days.

**PREDNISOLONE SODIUM SUCCINATE** is administered as a powder for solution for injection, with a maximum daily dose of 6 mg and a total dose of 36 mg over 6 days. The chemical origin substance is delivered intrathecally.

**CYTARABINE** is provided as a solution for injection, with a maximum daily dose of 30 mg and a total dose of 180 mg over 6 days. The chemical origin substance is administered intrathecally.

**IMATINIB** is administered as a film-coated tablet, with a maximum daily dose of 340 mg/m² and a total dose of 252280 mg/m² over 106 days. The chemical origin substance is delivered orally.

**INOTUZUMAB OZOGAMICIN**, marketed as BESPONSA, is provided as a powder for concentrate for solution for infusion. This protein-based treatment is administered intravenously, with a maximum daily dose of 0.5 mg/m² and a total dose of 3 mg/m² over 6 days.

**METHYLPREDNISOLONE SODIUM SUCCINATE** is administered as a powder for injection, with a maximum daily dose of 4.8 mg and a total dose of 28.8 mg over 6 days. The chemical origin substance is delivered intrathecally.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **event-free survival (EFS)**, disease-free survival (DFS), and the fraction of patients with undetectable minimal residual disease (MRD) after one cycle of blinatumomab for patients with Down syndrome. These endpoints will be compared with historical control cohorts to evaluate the effectiveness of the interventions.

Secondary endpoints focus on overall survival (OS), rates of death during induction, resistant disease, and cumulative incidences of relapse, death in first complete remission, and second malignancy. Additionally, the study will assess treatment-related mortality, leukemia-specific mortality, and the incidence of adverse events of special interest. Quality of life (QoL) will be measured using EQ5D-based instruments at various stages of the trial to evaluate the impact of the interventions on patients' well-being.

For specific phases of the trial, such as R1 and R2, efficacy will be further evaluated through overall survival, cumulative incidence of relapse, and the fraction of surviving patients treated with allogeneic stem-cell transplant in second remission. Toxicity assessments will include rates of febrile neutropenia, invasive fungal infections, serious viral reactivation, and other non-lethal toxicities. These will be quantified by measuring hospital admission days, days on intravenous antibiotics, and other supportive care metrics.

Exploratory endpoints will include the CD22 expression level of leukemic cells in bone marrow samples and MRD response at specific timepoints. The trial will employ a combination of laboratory tests, patient-reported outcomes, and validated scales to collect and analyze data at designated intervals throughout the study duration.