Phase II Randomized Study of Bortezomib with Dexamethasone, Mitoxantrone, Vincristine, Pegaspargase, and Methotrexate in High-Risk Relapsed Pediatric ALL

The primary objective of this study is to evaluate the **improvement of CR2 rates** after induction therapy with ALL R3 incorporating **bortezomib** versus without bortezomib in patients with high-risk relapsed **Acute Lymphoblastic Leukemia (ALL)**. This is clinically relevant as achieving a higher CR2 rate can significantly impact the prognosis and long-term survival of these patients, offering a potential advancement in the treatment of this aggressive form of leukemia.

Secondary objectives include:

• Improvement of event-free survival (EFS) and overall survival (OS) rates.
• Enhancement of minimal residual disease (MRD) reduction post-induction with versus without bortezomib.
• Improvement of MRD load prior to stem cell transplantation (SCT).
• Increasing the proportion of high-risk patients reaching SCT.
• Assessing the prognostic relevance of MRD before SCT.
• Improvement of CR2 and/or MRD rates during consolidation.
• Evaluation of the toxicity of induction therapy with versus without bortezomib.

The clinical trial involves a total of **11 participants** diagnosed with **Relapsed Acute Lymphoblastic Leukemia (ALL)**. The study population comprises both male and female children under the age of 18, who have a morphologically confirmed diagnosis of first relapsed precursor B-cell or T-cell ALL. Participants were selected based on specific high-risk criteria, including any T bone marrow relapse, early or very early isolated bone marrow relapse, and very early isolated or combined extramedullary relapse. The trial does not include a vulnerable population. Participants are required to have written informed consent and must not have participated in other clinical trials that interfere with this protocol within 30 days prior to enrollment, except for trials related to primary ALL. The study does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is a **randomized**, **double-blind**, controlled Phase II study designed to evaluate the efficacy of adding **bortezomib** to standard chemotherapy in patients with high-risk relapsed **acute lymphoblastic leukemia** (ALL). The primary objective is to improve the second complete remission (CR2) rates after induction therapy. The trial is expected to run from March 2018 to August 2028, with participant involvement lasting up to 13 months, depending on the treatment arm and response to therapy.

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 previous treatment history. Following randomization, participants will be assigned to either the standard chemotherapy arm or the standard chemotherapy plus bortezomib arm. The trial includes multiple follow-up visits to monitor treatment response, adverse events, and overall health status. These visits will occur at regular intervals throughout the treatment period and will include assessments such as blood tests, imaging studies, and physical examinations.

The end-of-study visit will occur after the completion of the treatment regimen, where final evaluations will be conducted to assess the primary and secondary endpoints, including event-free survival (EFS), overall survival (OS), and minimal residual disease (MRD) rates. Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they choose to withdraw consent. The study is conducted in compliance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Dexamethasone phosphate Accord** is provided as a 4 mg/ml solution for injection or infusion. The active substance, **dexamethasone**, is administered intravenously with a maximum daily dose of 20 mg/m² and a total dose not exceeding 380 mg/m² over a treatment period of up to 11 weeks. This medication is chemically derived and is not a pediatric formulation.

**Mitoxantrone** is supplied as a 2 mg/ml concentrate for solution for infusion. The active substance, **mitoxantrone**, is delivered via intravenous infusion. The maximum daily dose is 10 mg/m², with a total dose capped at 20 mg/m², administered over a maximum treatment period of 1 week. This compound is also chemically derived and not formulated for pediatric use.

**Vincristine Sulfate** is available as a 1 mg/ml solution for injection or infusion. The active substance, **vincristine sulfate**, is administered through intravenous infusion. The maximum daily dose is 1.5 mg/m², with a total dose limit of 9 mg/m² over a treatment period of up to 11 weeks. This medication is chemically derived and not intended for pediatric patients.

**VELCADE**, containing the active substance **bortezomib**, is provided as a 3.5 mg powder for solution for injection. It is administered via IV injection or infusion, with a maximum daily dose of 1.3 mg/m² and a total dose not exceeding 5.2 mg/m² over a 3-week treatment period. This compound is chemically derived and not a pediatric formulation.

**Oncaspar** is supplied as a 750 U/ml powder for solution for injection or infusion. The active substance, **pegaspargase**, is administered through intravenous infusion. The maximum daily dose is 1000 IU, with a total dose limit of 4000 IU over a treatment period of up to 13 weeks. This medication is derived from a protein source and is not formulated for pediatric use.

**METHOTREXATE VIATRIS** is available as a 100 mg/ml solution for injection. The active substance, **methotrexate**, is delivered via intravenous infusion. The maximum daily dose is 1000 mg/m², with a total dose capped at 2000 mg/m² over a maximum treatment period of 1 week. This compound is chemically derived and not intended for pediatric patients.

Throughout the trial, participant compliance with dosing schedules is monitored to ensure adherence to the prescribed treatment regimens. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided.

The efficacy of the clinical trial will be assessed through the primary endpoint of improving the complete remission rate (CR2) after induction therapy in patients with high-risk relapsed acute lymphoblastic leukemia (ALL). This will be evaluated by comparing the CR2 rates between two treatment arms: standard chemotherapy with **bortezomib** (Arm B) and standard chemotherapy alone (Arm A). The assessment will be conducted using cytological analysis to quantify the remission rates.

Secondary endpoints include the improvement of three-year event-free survival (EFS) and overall survival (OS) rates, the rate of patients reaching hematopoietic stem cell transplantation (HSCT), and minimal residual disease (MRD) rates post-induction and pre-HSCT. The prognostic relevance of MRD pre-HSCT, CR2, and MRD rates during consolidation, as well as the toxicity of the randomized arms, will also be evaluated. These parameters will be measured at various timepoints throughout the trial to provide a comprehensive assessment of the treatment efficacy.