Evaluation of Bortezomib, Blinatumomab, and Methotrexate in Pediatric Acute Lymphoblastic Leukemia: A Randomized Controlled Trial

The primary objective of the study is to evaluate whether the **probability of event-free survival (pEFS)** can be improved in children and adolescents with acute lymphoblastic leukemia (ALL) through various treatment modifications. These include the addition of the proteasome inhibitor Bortezomib during an extended consolidation phase for early high-risk precursor B-cell ALL (pB-ALL), the incorporation of two cycles of post-consolidation immunotherapy with Blinatumomab for high-risk pB-ALL, the use of one cycle of post-reintensification immunotherapy with Blinatumomab for intermediate-risk pB-ALL, and the extension of the consolidation phase with increased doses of Cyclophosphamide, Cytarabine, and 6-Mercaptopurine for early non-standard risk T-cell ALL (T-ALL). These modifications aim to enhance treatment efficacy and improve survival outcomes, which are clinically significant for optimizing therapeutic strategies in pediatric ALL.

Secondary objectives include:

• Assessing whether overall survival can be improved by the treatment in the experimental arm.
• Determining the incidence of treatment-related toxicities and mortality in the experimental arm compared to the standard arm.
• Evaluating if the minimal residual disease (MRD) load after consolidation treatment can be reduced by additional treatment with Bortezomib.
• Investigating whether treatment-related life-threatening complications and mortality during the intensified consolidation phase of high-risk treatment can be reduced by replacing two intensive chemotherapy courses with two cycles of immunotherapy with Blinatumomab.
• Comparing the proportion of patients with insufficient MRD response to Blinatumomab as defined in the protocol with the MRD response after the HR-2' block in the control arm.
• Assessing if the MRD load after the first and second treatment cycles can be reduced in the experimental arm compared to conventional intensive chemotherapy.
• Determining the proportion of patients with positive MRD after reintensification Protocol II who become MRD-negative over the Blina cycle compared to 4 weeks of standard maintenance therapy, and evaluating if the MRD load after consolidation treatment can be reduced by extending the consolidation phase.
• Comparing the clinical outcome of standard-risk patients to that obtained for standard-risk patients in study AIEOP-BFM ALL 2009.

The clinical trial involves a total of **850 participants** diagnosed with **acute lymphoblastic leukemia** in children and adolescents. The study population includes both male and female subjects under the age of 18 years, specifically up to 17 years and 365 days at the time of diagnosis. Participants were selected based on their diagnosis of newly diagnosed acute lymphoblastic leukemia, mixed phenotype acute leukemia with specific lineage assignments, or acute undifferentiated leukemia. The trial includes a vulnerable population, as it involves children and adolescents. Participants are required to be enrolled in a participating center and have provided written informed consent for trial participation and data processing. The study does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided additional information regarding the general health status or specific lifestyle habits of the participants.

The clinical trial is designed to evaluate the efficacy and safety of various treatment regimens for **acute lymphoblastic leukemia** in children and adolescents. This is a Phase III, randomized, double-blind, controlled trial aimed at confirming the safety and efficacy of the treatments. The trial is expected to run from July 15, 2018, to July 14, 2028, with participant involvement lasting up to 56 days, depending on the treatment arm. The trial includes several randomization points to assess different therapeutic strategies, including the use of **bortezomib** and **blinatumomab** in specific patient subgroups.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age under 18 years, diagnosis of acute lymphoblastic leukemia, and informed consent. Following randomization, participants will attend follow-up visits to monitor treatment response and adverse events. The end-of-study visit will assess the primary endpoint, which is the time from randomization to the first event, such as relapse or death. Secondary endpoints include survival rates and treatment-related adverse events.

Participants may be withdrawn from the study early if they experience significant adverse effects, non-compliance with the protocol, or withdrawal of consent. The trial's design ensures rigorous monitoring and data collection to evaluate the potential benefits and risks of the investigational treatments, contributing valuable information to the field of pediatric oncology.

The clinical trial involves the administration of several experimental and non-experimental medications. **Prednisolone** is administered in an oral pharmaceutical form, with a maximum daily dose of 60 mg/m² and a total dose of 1837.5 mg/m² over a treatment period of 37 days. It is a chemical-origin medication used in the trial as a standard treatment.

**Betamethasone Sodium Phosphate** is provided in both oral and intravenous forms, with the same dosing schedule as Prednisolone. This medication is also of chemical origin and serves as a comparator treatment in the study.

**Doxorubicin Hydrochloride**, marketed as Myocet, is administered intravenously as a dispersion for infusion. The maximum daily dose is 50 mg/m², with a total dose of 250 mg/m² over 5 days. This chemical-origin drug is used as a standard treatment in the trial.

**Cyclophosphamide** is administered intravenously, with a maximum daily dose of 1000 mg/m² and a total dose of 6500 mg/m² over 41 days. It is a chemical-origin medication used as a standard treatment.

**Crisantaspase**, marketed as Erwinase, is administered either via intravenous infusion or intramuscular injection. The maximum daily dose is 20,000 IU, with a total dose of 1,260,000 IU over 40 days. This protein-origin medication is used as a standard treatment.

**Daunorubicin Hydrochloride** is administered intravenously, with a maximum daily dose of 30 mg/m² and a total dose of 150 mg/m² over 14 days. It is a chemical-origin medication used as a standard treatment.

**Fludarabine** is administered intravenously, with a maximum daily dose of 30 mg/m² and a total dose of 150 mg/m² over 5 days. This chemical-origin drug is used as a standard treatment.

**Methotrexate Sodium** is administered intrathecally, with a maximum daily dose of 12 mg and a total dose of 312 mg over 66 days. It is a chemical-origin medication used as a standard treatment.

**Dexamethasone Acetate** is administered both orally and intravenously, with a maximum daily dose of 20 mg/m² and a total dose of 1035 mg/m² over 42 days. This chemical-origin drug is used as a standard treatment.

**Vindesine Sulfate** is administered intravenously, with a maximum daily dose of 5 mg and a total dose of 10 mg over 5 days. It is a chemical-origin medication used as a standard treatment.

**Pegaspargase**, marketed as Oncaspar, is administered intravenously, with a maximum daily dose of 3750 IU and a total dose of 33,750 IU over 40 days. This protein-origin medication is used as a standard treatment.

**Tioguanine** is administered orally, with a maximum daily dose of 60 mg/m² and a total dose of 840 mg/m² over 14 days. It is a chemical-origin medication used as a standard treatment.

**Vinorelbine** is administered intravenously, with a maximum daily dose of 2 mg and a total dose of 28 mg over 44 days. This chemical-origin drug is used as a standard treatment.

**Etoposide** is administered intravenously, with a maximum daily dose of 200 mg/m² and a total dose of 500 mg/m² over 3 days. It is a chemical-origin medication used as a standard treatment.

**Mercaptopurine** is administered orally, with a maximum daily dose of 100 mg/m² and a total dose of 54,320 mg/m² over 23 weeks. This chemical-origin drug is used as a standard treatment.

**Bortezomib** is administered intravenously, with a maximum daily dose of 1.3 mg/m² and a total dose of 5.2 mg/m² over 10 days. It is a chemical-origin medication used as a standard treatment.

**Blinatumomab**, marketed as Blincyto, is administered intravenously as a solution for infusion. The maximum daily dose is 28 µg, with a total dose of 1568 µg over 56 days. This protein-origin medication is used as a standard treatment.

**Etoposide Phosphate** is administered intravenously, with a maximum daily dose of 200 mg/m² and a total dose of 500 mg/m² over 3 days. It is a chemical-origin medication used as a standard treatment.

**Ifosfamide** is administered intravenously, with a maximum daily dose of 1600 mg/m² and a total dose of 4000 mg/m² over 3 days. This chemical-origin drug is used as a standard treatment.

**Cytarabine** is administered intravenously, with a maximum daily dose of 2000 mg/m² and a total dose of 15,600 mg/m² over 39 days. It is a chemical-origin medication used as a standard treatment.

The efficacy of the clinical trial will be assessed using specific primary and secondary endpoints. The primary endpoints include the time from randomization until the first event, which is defined as cytomorphological or molecular non-response, relapse, second malignancy, or death from any cause. This is referred to as Event-Free Survival (EFS) time for Randomization R-eHR, R-HR, and R-T, and Disease-Free Survival (DFS) time for Randomization R-MR. The secondary endpoints will evaluate survival starting at the same time point as EFS/DFS, the frequency and incidence of treatment-related mortality during induction or continuous complete remission (CCR), and the frequency and incidence of adverse events (AE) and serious adverse events (SAE) during specific protocol phases, randomized arms, and overall follow-up. Additionally, the secondary endpoints will assess the **Minimal Residual Disease (MRD)** load after the randomized treatment phases and the proportion of patients with poor MRD response to the first Blinatumomab cycle.