Phase III Randomized Study of Bortezomib and Blinatumomab with Methotrexate in Pediatric Acute Lymphoblastic Leukemia

The primary objective of this randomized phase III study is to evaluate the efficacy of additional therapy in children with early high-risk (early HR) **acute lymphoblastic leukemia** (pB-ALL) defined by genetics and/or inadequate treatment response during induction. Specifically, the study aims to determine if the probability of event-free survival (pEFS) from the time of randomization can be improved by incorporating the proteasome inhibitor **Bortezomib** during an extended consolidation treatment phase compared to standard extended consolidation. Additionally, the study seeks to assess whether immunotherapy with **Blinatumomab** plus intrathecal **Methotrexate** can decrease the frequency of life-threatening treatment-related toxicities without reducing the frequency of achieving negative minimal residual disease (MRD) compared to the standard post-consolidation chemotherapy regimen. These objectives are clinically relevant as they aim to enhance treatment outcomes and reduce adverse effects in pediatric patients with high-risk leukemia.

Secondary objectives include: - Evaluating if overall survival can be improved by treatment in the experimental arm. - Comparing the incidence of treatment-related toxicities and mortality between the experimental and standard arms. - Assessing if the MRD load after consolidation treatment can be reduced by additional treatment with **Bortezomib**. - Determining the change in MRD load associated with treatment with **Blinatumomab** compared to standard high-risk blocks. - Analyzing the dynamics of MRD load in children treated with **Blinatumomab** at predefined timepoints compared to those receiving standard high-intensity post-consolidation therapy. - Evaluating the proportion of patients with poor response to **Blinatumomab** as defined in the protocol compared to the MRD response after the HR-1’ and HR-2’ block in the control arm. - Investigating the clinical outcomes, including the frequency of MRD-negativity, probability of event-free survival (pEFS), and probability of overall survival (pOS) in patients randomized to **Blinatumomab** compared with those randomized to standard HR-blocks joined with historic patients receiving HR-blocks according to the same protocol. - Comparing the clinical outcomes of patients treated in experimental arms to those treated in control arms of the original AIEOP-BFM ALL 2017 study.

The clinical trial involves a study population of children diagnosed with **acute lymphoblastic leukemia** (ALL), acute undifferentiated leukemia, or mixed phenotype acute leukemia (MPAL) with specific criteria. Participants are under the age of 18, with the age range extending up to 17 years and 365 days at the time of diagnosis. The trial includes both male and female subjects, and the population is considered vulnerable due to the pediatric nature of the participants. The sponsor has not provided the total number of participants involved in the study. Participants were selected based on their diagnosis and enrollment in a participating center, with informed consent obtained for trial participation and data processing. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Key inclusion criteria focus on the diagnosis of leukemia and age, while exclusion criteria are not detailed in the provided data.

The clinical trial is designed to evaluate the efficacy and safety of various treatment regimens for children and adolescents with **acute lymphoblastic leukemia**. This is a randomized, phase III study conducted in collaboration with the AIEOP-BFM study group. The trial employs a double-blind, controlled methodology to ensure unbiased results. The estimated duration of the trial is from June 2021 to August 2029, with participant involvement expected to last up to 115 weeks, depending on the treatment arm and individual response.

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 consent. The trial includes multiple follow-up visits to monitor treatment response and adverse events. These visits are scheduled at key intervals throughout the treatment phases, including induction, consolidation, and post-consolidation. The end-of-study visit will assess the overall outcomes and any long-term effects of the treatment.

The trial involves two main randomization points: R-eHR and R-HR. The R-eHR randomization evaluates the addition of the proteasome inhibitor **bortezomib** during an extended consolidation phase, while the R-HR randomization assesses the use of **blinatumomab** in combination with intrathecal **methotrexate** to reduce treatment-related toxicities. Primary endpoints include event-free survival (EFS) and the frequency of grade 4 adverse events. Secondary endpoints focus on overall survival (OS), minimal residual disease (MRD) negativity, and the incidence of adverse events.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the protocol, or if the investigator deems it in their best interest. The trial aims to provide valuable insights into optimizing treatment strategies for acute lymphoblastic leukemia, potentially improving patient outcomes and reducing treatment-related complications.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, routes, and frequencies of administration. **Blinatumomab** is provided as a solution for infusion, administered intravenously. The dosage is 15 µg/m² per day, with a maximum total dose of 1260 µg/m² over a treatment period of 84 days. This medication is classified as an antineoplastic agent.

**Bortezomib** is administered as a powder for solution for injection, also intravenously. The dosage is 1.3 mg/m², with a maximum total dose of 5.2 mg/m² over a 4-day treatment period. It is used as an antineoplastic agent.

**Prednisone** is provided in tablet form for oral administration. The dosage is 60 mg/m², with a maximum total dose of 1837.5 mg/m² over a 37-day treatment period. It is classified as a glucocorticoid.

**Ifosfamide** is administered as a powder for solution for injection, intravenously. The dosage is 800 mg/m², with a maximum total dose of 4000 mg/m² over a 3-day treatment period. It is an antineoplastic agent.

**Crisantaspase** is provided as a powder for solution/suspension for injection, administered intravenously. The dosage is 20000 IU, with a maximum total dose of 1260000 IU over a 63-day treatment period. It is classified as an antineoplastic agent.

**Etoposide** is administered as a concentrate for solution for infusion, intravenously. The dosage is 100 mg/m², with a maximum total dose of 500 mg/m² over a 3-day treatment period. It is used as an antineoplastic agent.

**Prednisolone** is provided in tablet form for oral administration. The dosage is 60 mg/m², with a maximum total dose of 1837.5 mg/m² over a 37-day treatment period. It is classified as a glucocorticoid.

**Dexamethasone** is administered in tablet form for oral use. The dosage is 20 mg/m², with a maximum total dose of 1040 mg/m² over a 115-day treatment period. It is classified as a glucocorticoid.

**Cyclophosphamide** is provided as a powder for solution for injection, administered intravenously. The dosage is 1000 mg/m², with a maximum total dose of 5500 mg/m² over a 9-day treatment period. It is an antineoplastic agent.

**Prednisolone Sodium Succinate** is administered as a powder and solvent for solution for injection/infusion, intravenously. The dosage is 60 mg/m², with a maximum total dose of 1837.5 mg/m² over a 37-day treatment period. It is classified as a glucocorticoid.

**Methotrexate** is provided in tablet form for oral administration. The dosage is 20 mg/m², with a maximum total dose of 1600 mg/m² over an 80-day treatment period. It is used as an antineoplastic agent.

**Vincristine Sulfate** is administered as a solution for injection, intravenously. The dosage is 2 mg, with a maximum total dose of 28 mg over a 14-day treatment period. It is an antineoplastic agent.

**Doxorubicin Hydrochloride** is provided as a concentrate for solution for infusion, administered intravenously. The dosage is 30 mg/m², with a maximum total dose of 180 mg/m² over a 6-day treatment period. It is classified as an antineoplastic agent.

**Methotrexate Disodium** is administered as a solution for injection, via intrathecal use. The dosage is 12 mg, with a maximum total dose of 312 mg over a 26-day treatment period. It is used as an antineoplastic agent.

**Dexamethasone Phosphate** is provided as a solution for injection/infusion, administered intravenously. The dosage is 20 mg/m², with a maximum total dose of 115 mg/m² over a 115-day treatment period. It is classified as a glucocorticoid.

**Cytarabine** is administered as a solution for injection, intravenously. The dosage is 2000 mg/m², with a maximum total dose of 15000 mg/m² over a 43-day treatment period. It is an antineoplastic agent.

**Pegaspargase** is provided as a powder for solution for injection/infusion, administered intravenously. The dosage is 3750 IU, with a maximum total dose of 33750 IU over a 9-day treatment period. It is classified as an antineoplastic agent.

**Vindesine Sulfate** is administered as a powder for solution for injection, intravenously. The dosage is 3 mg/m², with a maximum total dose of 6 mg/m² over a 2-day treatment period. It is an antineoplastic agent.

**Mercaptopurine** is provided in tablet form for oral administration. The dosage is 50 mg/m², with a maximum total dose of 31080 mg/m² over a 644-day treatment period. It is used as an antineoplastic agent.

**Daunorubicin Hydrochloride** is administered as a solution for injection, intravenously. The dosage is 30 mg/m², with a maximum total dose of 150 mg/m² over a 5-day treatment period. It is classified as an antineoplastic agent.

**Tioguanine** is provided in tablet form for oral administration. The dosage is 60 mg/m², with a maximum total dose of 2520 mg/m² over a 42-day treatment period. It is used as an antineoplastic agent.

**Fludarabine Phosphate** is administered as a concentrate for solution for injection/infusion, intravenously. The dosage is 30 mg/m², with a maximum total dose of 150 mg/m² over a 5-day treatment period. It is classified as an antineoplastic agent.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the time from randomization until the first event, such as cytomorphological or molecular non-response, relapse, second malignancy, or death from any cause, collectively referred to as Event-Free Survival (EFS) time. Additionally, the frequency and incidence of grade 4 adverse events or death from any cause, as well as the frequency of patients achieving negative Minimal Residual Disease (MRD) after specific treatment cycles, will be evaluated.

Secondary endpoints will focus on various aspects, including the time from randomization to death from any cause, the frequency and incidence of grade 4 adverse events during specific treatment phases, and the proportion of children with negative MRD at designated timepoints. The trial will also measure the absolute difference in MRD load between different treatment phases and the time from the first day of treatment to events such as death, relapse, secondary malignancy, or molecular non-response.

These endpoints will be measured and analyzed at specific timepoints throughout the trial, including after the first and third cycles of **Blinatumomab** or after the HR-1’/HR-3’ block. The trial aims to determine whether additional therapy with the proteasome inhibitor **Bortezomib** or immunotherapy with **Blinatumomab** can improve outcomes in children with high-risk acute lymphoblastic leukemia (ALL) without increasing the frequency of life-threatening treatment-related toxicities.