Efficacy of Ponatinib and Blinatumomab Versus Chemotherapy and Imatinib in Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

The primary objective of this study is to evaluate the efficacy of a front-line **chemo-free** strategy in adult patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL). This strategy involves the administration of Ponatinib plus steroids as induction treatment, followed by Blinatumomab infusion as consolidation. The efficacy will be compared to a chemotherapy regimen combined with Imatinib, focusing on event-free survival (EFS). EFS is a composite endpoint that includes non-achievement of minimal residual disease (MRD) negativity, deaths from any cause, toxicity, and resistance, including resistance due to ABL1 mutation development. This is clinically relevant as it aims to improve treatment outcomes and reduce the adverse effects associated with traditional chemotherapy.

Secondary objectives include:

• Feasibility of patient stratification for allogeneic stem cell transplantation (allo-SCT) based on refined MRD evaluation and genetic lesions.
• Capability of Blinatumomab to further reduce MRD levels post-Ponatinib induction.
• Duration of complete molecular response (CMR) or positive not-quantifiable (PNQ) status.
• Disease-free survival (DFS) at 1 and 3 years.
• Overall survival (OS) at 1 and 3 years.
• Cumulative incidence of relapse (CIR).
• Safety profile of the treatment.
• Comparison of patients' quality of life (QoL) profiles over time by randomization arms.
• Achievement and duration of CMR, OS, and DFS according to clinical, biological, and molecular characteristics at baseline, including type of fusion protein and additional genomic lesions.

The clinical trial involves participants diagnosed with **Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia**. The study population includes both male and female adults aged 18 years and older, with no upper age limit specified. Participants are required to have a WHO performance status of 2 or less, indicating a relatively stable general health status. The trial population was selected based on specific inclusion criteria, such as newly diagnosed B-precursor Ph+ ALL patients, normal cardiac function, and adequate renal, hepatic, and pancreatic function. Additionally, participants must have a negative HIV test and no evidence of CNS leukemia at the start of blinatumomab treatment. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of a sequential treatment approach for **Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia** (Ph+ ALL). This study employs a **randomized, double-blind, controlled** design to compare the administration of **Ponatinib** and **Blinatumomab** against a chemotherapy regimen combined with **Imatinib**. The trial aims to assess event-free survival (EFS) as the primary endpoint, with events defined as non-achievement of minimal residual disease (MRD) negativity, deaths, toxicity, and resistance. The trial is expected to run from April 2021 to February 2028, with participant involvement lasting up to 40 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), renal and hepatic function, and absence of central nervous system leukemia. Following the screening, participants will be randomized into one of the two treatment arms. The study includes multiple follow-up visits to monitor treatment response, adverse events, and MRD status. The end-of-study visit will evaluate the overall treatment efficacy and safety profile.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial's secondary endpoints include the feasibility of stratifying patients for allogeneic stem cell transplantation based on MRD evaluation, the capability of Blinatumomab to reduce MRD levels post-Ponatinib induction, and overall survival (OS) at 1 and 3 years. The study will also assess the safety profile and quality of life (QoL) of participants over time.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Ponatinib**, marketed as Iclusig, is administered in the form of 15 mg film-coated tablets. The route of administration is oral, with a maximum daily dose of 45 mg and a total dose not exceeding 12.6 grams over a treatment period of 40 days. Ponatinib is a chemical substance used as part of the experimental treatment strategy.

**Blinatumomab**, marketed as BLINCYTO, is provided as a 38.5 micrograms powder for concentrate and solution for infusion. It is administered via infusion, with a maximum daily dose of 28 micrograms and a total dose of 3920 micrograms over a 20-day treatment period. Blinatumomab is a protein-based treatment used in the experimental arm of the study.

**Vincristine Sulfate** is administered as a 1 mg/ml solution for injection. The route of administration is intravenous, with a maximum daily dose of 2 mg/m² and a total dose of 28 mg/m² over a 14-day period. This chemical substance is part of the standard chemotherapy regimen.

**Melphalan Hydrochloride** is provided as a 50 mg powder and solvent for solution for injection/infusion. It is administered intravenously, with a maximum daily and total dose of 100 mg/m² over a single day. Melphalan is a chemical substance used in the chemotherapy regimen.

**Imatinib**, marketed as Glivec, is administered in the form of 100 mg hard capsules. The route of administration is oral, with a maximum daily dose of 800 mg and a total dose of 360.4 grams over a 30-day treatment period. Imatinib is a chemical substance used in the control arm of the study.

**Levetiracetam**, marketed as Keppra, is administered as 250 mg film-coated tablets. The route of administration is oral, with a maximum daily dose of 1000 mg and a total dose of 145 grams over a 145-day treatment period. Levetiracetam is a chemical substance used as an auxiliary treatment.

**Methotrexate** is administered as a solution for injection. The route of administration is intravenous, with a maximum daily dose of 12.5 mg and a total dose of 125 mg over a 10-day treatment period. Methotrexate is a chemical substance used as part of the standard treatment regimen.

**Idarubicin Hydrochloride**, marketed as Idarubicina Sandoz, is provided as a 1 mg/ml concentrate for solution for infusion. It is administered intravenously, with a maximum daily dose of 10 mg/m² and a total dose of 40 mg/m² over a 4-day period. Idarubicin is a chemical substance used in the chemotherapy regimen.

**Prednisone** is administered in tablet form. The route of administration is oral, with a maximum daily dose of 60 mg/m² and a total dose of 1915 mg/m² over a 38-day treatment period. Prednisone is a chemical substance used as an auxiliary treatment.

**Dexamethasone Sodium Phosphate** is provided as a 4 mg/ml solution for injection. It is administered intravenously, with a maximum daily dose of 10 mg/m² and a total dose of 250 mg/m² over a 25-day period. Dexamethasone is a chemical substance used in the chemotherapy regimen.

**Mercaptopurine**, marketed as PURINETHOL, is administered in tablet form. The route of administration is oral, with a maximum daily dose of 75 mg/m² and a total dose of 23310 mg/m² over a 27-day treatment period. Mercaptopurine is a chemical substance used in the chemotherapy regimen.

**Calcium Levofolinate**, marketed as LEDERFOLIN, is provided as a 25 mg powder for solution for injection. It is administered intravenously, with a maximum daily dose of 37.5 mg/m² and a total dose of 450 mg/m² over a 6-day period. Calcium Levofolinate is a chemical substance used in the chemotherapy regimen.

**Cyclophosphamide** is administered as a powder for solution for injection/infusion. The route of administration is intravenous, with a maximum daily dose of 750 mg/m² and a total dose of 2250 mg/m² over a 3-day period. Cyclophosphamide is a chemical substance used in the chemotherapy regimen.

**Filgrastim** is administered as a solution for injection. The route of administration is subcutaneous, with a maximum daily dose of 5 µg/kg and a total dose of 645 µg/kg over a 6-day period. Filgrastim is a protein-based treatment used as an auxiliary treatment.

**Cytarabine** is administered as a powder and solvent for solution for injection. The route of administration is intravenous, with a maximum daily dose of 50 mg and a total dose of 750 mg over a 15-day period. Cytarabine is a chemical substance used in the chemotherapy regimen.

**Methylprednisolone Sodium Succinate** is administered as a powder and solvent for solution for injection. The route of administration is intravenous, with a maximum daily dose of 20 mg and a total dose of 300 mg over a 15-day period. Methylprednisolone is a chemical substance used as an auxiliary treatment.

The efficacy of the clinical trial will be assessed using a primary endpoint of **event-free survival (EFS)**. This composite endpoint includes events such as non-achievement of minimal residual disease (MRD) negativity, deaths from any cause, toxicity, and resistance, including resistance due to ABL1 mutation development, in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The trial aims to compare the efficacy of a sequential treatment approach using Ponatinib and Blinatumomab against a chemotherapy regimen combined with Imatinib.

Secondary endpoints will include the feasibility of stratifying patients for allogeneic stem cell transplantation (allo-SCT) based on refined MRD evaluation and the presence or absence of IKZF1-plus. Additionally, the trial will assess the capability of Blinatumomab to further reduce MRD levels following Ponatinib induction, the duration of complete molecular response (CMR) or partial negative quantification (PNQ), disease-free survival (DFS) at 1 and 3 years, overall survival (OS) at 1 and 3 years, and cumulative incidence of relapse (CIR). The safety profile will be evaluated in terms of the incidence of grade ≥3 CTC-NCI side effects and toxicities. Furthermore, the trial will compare patients' quality of life (QoL) profiles over time across the randomization arms.