Phase 3 Study of Imatinib with Cytotoxic Chemotherapy in Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

The primary objective of this international phase 3 trial is to compare **disease-free survival (DFS)** in pediatric patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who are classified as Standard Risk (SR). The study evaluates the efficacy of continuous **imatinib** in combination with two different chemotherapy backbones: a high-risk COG ALL chemotherapy regimen and the more intensive EsPhALL chemotherapy regimen. This comparison is clinically relevant as it aims to determine the most effective treatment strategy to improve DFS in this specific patient population, potentially leading to better long-term outcomes and survival rates.

The clinical trial involves a study population diagnosed with **acute lymphoblastic leukemia** (ALL), specifically focusing on pediatric patients with Philadelphia chromosome-positive (Ph+) ALL. The participants are both male and female, aged between 1 and 21 years at the time of diagnosis. The trial includes individuals who are considered part of a vulnerable population due to their age and health condition. Participants must have a performance status corresponding to ECOG scores of 0, 1, or 2, indicating they are fully active or have some restrictions but are ambulatory. They must also have adequate liver, cardiac, and renal function. The trial population was selected based on their enrollment in a National ALL protocol and the availability of baseline diagnostic samples for MRD probe development. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the efficacy of **imatinib** in combination with two different cytotoxic chemotherapy backbones in patients with Philadelphia chromosome-positive **acute lymphoblastic leukemia** (Ph+ ALL). The primary objective is to compare disease-free survival (DFS) in standard-risk pediatric patients treated with continuous imatinib combined with either a high-risk COG ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone. The trial is expected to run from September 20, 2017, to January 31, 2027, with an estimated duration of 10 years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, diagnosis, and prior therapy. The inclusion criteria specify that patients must be between 1 and 21 years old at diagnosis, have a new diagnosis of BCR-ABL1 fusion or ABL-class fusion, and meet specific therapy requirements. Follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse events. The end-of-study visit will conclude the trial, assessing the primary endpoint of DFS, defined as the time from randomization to the first event (relapse, second malignancy, or death in complete remission) or time to last follow-up for patients without events.

The expected length of participant involvement varies depending on the treatment regimen, with the maximum treatment period for **imatinib** being 730 days. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or failure to comply with the study protocol. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, routes, and frequencies of administration. **Tioguanine** is administered in tablet form, with a maximum daily dose of 60 mg/m² and a total dose of 1680 mg/m² over a 28-day period. The route of administration is oral. **Imatinib** is provided as a film-coated tablet, with a maximum daily dose of 800 mg and a total dose of 584,000 mg over 730 days, also administered orally.

**Doxorubicin Hydrochloride** is administered as a solution for injection, with a maximum daily dose of 25 mg/m² and a total dose of 200 mg/m² over 8 days. The route is injection. **Pegaspargase** is given as a solution for infusion, with a maximum daily dose of 2500 m² and a total dose of 12,500 m² over 5 days, administered via infusion.

**Cytarabine** is used in two forms: a solution for injection or infusion with a maximum daily dose of 30 mg and a total dose of 90 mg over 3 days, administered intrathecally, and a suspension for injection with a maximum daily dose of 4000 mg/m² and a total dose of 14,400 mg/m² over 4 days, administered via injection.

**Dexamethasone** is administered in tablet form, with a maximum daily dose of 20 mg/m² and a total dose of 860 mg/m² over 110 days, administered orally and intravenously. **Prednisone**, marketed as Deltacortene 25 mg compresse, is also administered in tablet form, with a maximum daily dose of 60 mg/m² and a total dose of 840 mg/m² over 2 days, administered orally and intravenously.

**Mercaptopurine** is administered in tablet form, with a maximum daily dose of 75 mg/m² and a total dose of 40,500 mg/m² over 18 days, administered orally. **Crisantaspase**, marketed as Erwinase 10,000 U, is administered as a solution for injection or infusion, with a maximum daily dose of 40,000 IU and a total dose of 1,400,000 IU over 10 days, administered intravenously.

**Daunorubicin Hydrochloride** is administered as a solution for injection, with a maximum daily dose of 30 mg/m² and a total dose of 80 mg/m² over 3 days, administered via injection. **Ifosfamide** is administered as a solution for infusion, with a maximum daily dose of 1600 mg/m² and a total dose of 4000 mg/m² over 3 days, administered via infusion.

**Methotrexate** is administered in three forms: a solution for injection in a pre-filled syringe with a maximum daily dose of 12 mg and a total dose of 216 mg over 18 days, administered intravenously, intra-arterially, and intrathecally; a tablet form with a maximum daily dose of 30 mg/m² and a total dose of 1500 mg/m² over 16 days, administered orally; and a concentrate for solution for infusion with a maximum daily dose of 5000 mg/m² and a total dose of 21,000 mg/m² over 9 days, administered via infusion.

**Cyclophosphamide** is administered as an injection/infusion, with a maximum daily dose of 1 mg/m² and a total dose of 5 mg/m² over 5 days, administered via injection. **Etoposide** is administered as a solution for infusion, with a maximum daily dose of 200 mg/m² and a total dose of 500 mg over 3 days, administered via infusion.

**Vincristine Sulfate**, marketed as Vincristina Teva Italia 1 mg/ml, is administered as an injection, with a maximum daily dose of 2 mg and a total dose of 36 mg/m² over 24 days, administered via injection. **Prednisolone**, marketed as Decortin H 5 mg töflur, is administered in tablet form, with a maximum daily dose of 60 mg/m² and a total dose of 840 mg/m² over 2 days, administered orally.

**Hydrocortisone Sodium Succinate** is administered as a solution for injection/infusion, with a maximum daily dose of 12 mg and a total dose of 36 mg over 3 days, administered intrathecally. Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols.

Efficacy in this clinical trial will be assessed primarily through the measurement of **disease-free survival (DFS)**. DFS is defined as the time from randomization to the first event, which may include relapse, the occurrence of a second malignancy, or death while in complete remission. For patients who do not experience any of these events, DFS will be measured up to the time of the last follow-up. This endpoint is critical in evaluating the effectiveness of the treatment regimen being tested, which involves the use of **imatinib** in combination with two different cytotoxic chemotherapy backbones for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).